Journal articles: 'Soluble CD89'

1

Launay, Pierre, Béatrice Grossetête, Michelle Arcos-Fajardo, Emmanuelle Gaudin, Sonia P. Torres, Lucie Beaudoin, Natacha Patey-Mariaud de Serre, Agnès Lehuen, and Renato C. Monteiro. "Fcα Receptor (Cd89) Mediates the Development of Immunoglobulin a (Iga) Nephropathy (Berger's Disease)." Journal of Experimental Medicine 191, no. 11 (June 6, 1999): 1999–2010. http://dx.doi.org/10.1084/jem.191.11.1999.

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The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgA1 complexes. However, the molecular mechanism(s) of the disease remain poorly understood. We report here the presence of circulating soluble FcαR (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRγ chain. The disease was induced in recombination activating gene (RAG)2−/− mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.

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van Zandbergen, Ger, Ralf Westerhuis, Ngaisah Klar Mohamad, Jan G. J. van de Winkel, Mohamed R. Daha, and Cees van Kooten. "Crosslinking of the Human Fc Receptor for IgA (FcαRI/CD89) Triggers FcR γ-Chain-Dependent Shedding of Soluble CD89." Journal of Immunology 163, no. 11 (December 1, 1999): 5806–12. http://dx.doi.org/10.4049/jimmunol.163.11.5806.

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Abstract CD89/FcαRI is a 55- to 75-kDa type I receptor glycoprotein, expressed on myeloid cells, with important immune effector functions. At present, no information is available on the existence of soluble forms of this receptor. We developed an ELISA for the detection of soluble CD89 (sCD89) forms and investigated the regulation of sCD89 production. PMA/ionomycin stimulation of monocytic cell lines (U937, THP-1, and MM6), but not of neutrophils, resulted in release of sCD89. Crosslinking of CD89 either via its ligand IgA or with anti-CD89 mAbs similarly resulted in sCD89 release. Using CD89-transfected cells, we showed ligand-induced shedding to be dependent on coexpression of the FcR γ-chain subunit. Shedding of sCD89 was dependent on signaling via the γ-chain and prevented by addition of inhibitors of protein kinase C (staurosporine) or protein tyrosine kinases (genistein). Western blotting revealed sCD89 to have an apparent molecular mass of 30 kDa and to bind IgA in a dose-dependent fashion. In conclusion, the present data document a ligand-binding soluble form of CD89 that is released upon activation of CD89-expressing cells. Shedding of CD89 may play a role in fine-tuning CD89 immune effector functions.

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Esteve Cols, Clara, Freddzia-Amanda Graterol Torres, Bibiana Quirant Sánchez, Helena Marco Rusiñol, Maruja Isabel Navarro Díaz, Jordi Ara del Rey, and Eva Mª Martínez Cáceres. "Immunological Pattern in IgA Nephropathy." International Journal of Molecular Sciences 21, no. 4 (February 18, 2020): 1389. http://dx.doi.org/10.3390/ijms21041389.

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The current gold-standard diagnostic technique for IgA nephropathy (IgAN), the leading form of primary glomerulonephritis, is renal biopsy. CD89 (the main IgA receptor) is expressed on the surface of monocytes and plays a role in disease pathogenesis. Immunocomplexes formed by sCD89 (soluble form) and Gd-IgA1 are related to disease prognosis. We hypothesize that reduced CD89 surface expression on monocytes may be a marker of disease severity. We aimed to analyze leukocyte subpopulations in peripheral blood and CD89 surface expression on monocytes in a prospective study of 22 patients and 12 healthy subjects (HS). Leukocyte subpopulations and CD89 expression were analyzed by flow cytometry. IgAN patients had a higher percentage of activated and effector memory CD4+ and CD8+ T lymphocytes, a lower percentage of transitional B lymphocytes and plasmablasts, and a higher percentage of CD56dimCD16+ NK cells and myeloid dendritic cells compared with HS. Correlations between reduced CD89 expression levels on nonclassical monocytes, histological findings of a poor prognosis on renal biopsy and baseline renal function were observed. IgAN patients show a characteristic immunological pattern in peripheral blood. A reduced expression level of CD89 on nonclassical monocytes identifies patients with a worse renal prognosis.

4

Wu, Haiting, Xiaoyan Wang, Zhe Yang, Qing Zhao, Yubing Wen, Xuemei Li, Wei Zhang, and Ruitong Gao. "Serum Soluble CD89-IgA Complexes Are Elevated in IgA Nephropathy without Immunosuppressant History." Disease Markers 2020 (January 16, 2020): 1–6. http://dx.doi.org/10.1155/2020/8393075.

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Purpose. CD89 (FcαRI), the receptor of IgA, can shed from cells to form complexes with IgA in serum and is supposed to participate in the pathogenesis of IgA nephropathy (IgAN). There are contradictory results on their utility in clinical practice. This study is aimed at investigating whether sCD89-IgA complexes can help in the diagnosis or evaluation of the disease. Methods. A sandwich ELISA was established using anti-CD89 as a capture antibody and HRP-conjugated anti-IgA as a detection antibody. This method was used to measure serum levels of sCD89-IgA complexes in IgAN patients without immunosuppressant history and healthy subjects. Correlations between serum levels of sCD89-IgA complexes and disease severity were analyzed. Results. Serum sCD89-IgA complexes increased with age (P<0.001). IgAN patients had higher sCD89-IgA complex levels compared with age- and gender-matched normal healthy individuals (P<0.001). Serum sCD89-IgAN significantly predicted IgAN diagnosis (AUC = 0.762 (0.640-0.883), P<0.001). But sCD89-IgA complexes did not correlate with baseline clinical manifestations, oxford classification, or renal function deteriorate speed. Conclusions. Serum sCD89-IgA complexes can guide diagnosis of IgAN in patients without immunosuppressant history, but provide limited help in clinicopathologic prediction.

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Cambier, Alexandra, Patrick J. Gleeson, Lilia Abbad, Fanny Canesi, Jennifer da Silva, Julie Bex-Coudrat, Georges Deschênes, et al. "Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy." Kidney International 101, no. 2 (February 2022): 274–87. http://dx.doi.org/10.1016/j.kint.2021.09.023.

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Berthelot, Laureline, Thomas Robert, Vincent Vuiblet, Thierry Tabary, Antoine Braconnier, Moustapha Dramé, Olivier Toupance, Philippe Rieu, Renato C. Monteiro, and Fatouma Touré. "Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes." Kidney International 88, no. 4 (October 2015): 815–22. http://dx.doi.org/10.1038/ki.2015.158.

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Vuong, Mai T., Mirjana Hahn-Zoric, Sigrid Lundberg, Iva Gunnarsson, Cees van Kooten, Lars Wramner, Maria Seddighzadeh, et al. "Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy." Kidney International 78, no. 12 (December 2010): 1281–87. http://dx.doi.org/10.1038/ki.2010.314.

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Hahn-Zoric, Mirjana, Mai Vuong, Sigrid Lundberg, Lars Wramner, Jarl Ahlmen, Lars Å. Hanson, Iva Gunnarsson, Stefan Jacobson, and Leonid Padyukov. "Su.82. Evidence for Genetic Regulation of Fc Alpha Receptor (CD89) Expression: Study of Soluble CD89 in Plasma of IgA Nephropathy Patients and Healthy Controls." Clinical Immunology 127 (January 2008): S151. http://dx.doi.org/10.1016/j.clim.2008.03.433.

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Hahn-Zoric, Mirjana, Neda Tahmasebifar, Cees van Kooten, Jarl Ahlmen, Svante Swerkersson, Sverker Hansson, Ulla Berg, Lars Åke Hanson, Leonid Padyukov, and Stefan H. Jacobson. "Immunoassays for Detection of Soluble Fc Alpha Receptor (CD89) in Plasma of IgA Nephropathy Patients." Clinical Immunology 123 (2007): S54—S55. http://dx.doi.org/10.1016/j.clim.2007.03.335.

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Berthelot, Laureline, Christina Papista, Thiago T. Maciel, Martine Biarnes-Pelicot, Emilie Tissandie, Pamela H. M. Wang, Houda Tamouza, et al. "Transglutaminase is essential for IgA nephropathy development acting through IgA receptors." Journal of Experimental Medicine 209, no. 4 (March 26, 2012): 793–806. http://dx.doi.org/10.1084/jem.20112005.

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IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA–soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1–sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89–TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1–sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1–sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.

11

Nockher, W. A., and J. E. Scherberich. "Expression and release of the monocyte lipopolysaccharide receptor antigen CD14 are suppressed by glucocorticoids in vivo and in vitro." Journal of Immunology 158, no. 3 (February 1, 1997): 1345–52. http://dx.doi.org/10.4049/jimmunol.158.3.1345.

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Abstract The effect of glucocorticoid (GC) treatment on expression and release of the monocyte cell surface LPS receptor Ag CD14 was studied in vivo and in vitro. In patients with acute inflammatory diseases receiving GC pulse therapy serum concentrations of soluble CD14 and CD14 expression by peripheral blood monocytes decreased significantly. The LPS-binding capacity correlated positively with the amount of cell surface CD14 by human blood monocytes. In vitro, a time- and dose-dependent effect of GC preparations on monocyte membrane and soluble CD14 by cultured peripheral blood monocytes was found. Incubation with 2 x 10(-8) M prednisolone down-regulated cell surface CD14 after 72 h, and 2 x 10(-7) M suppressed CD14 expression even after 24 h. Prednisolone also decreased release of the soluble CD14 Ag, where a 10-fold higher GC concentration was required for a significant suppression compared with membrane CD14 during culture. Expression of other monocyte membrane Ags were either unchanged (CD33, CD35), diminished (CD13, CD89), or increased (CD32) by GC, indicating no general down-modulation of cell surface Ag expression. Preincubation with glucocorticoids for 24 h significantly down-regulated CD14 expression during subsequent steroid-free culture for at least 7 days. In cultured monocytes, the LPS-induced increase of membrane and soluble CD14 was markedly but not completely inhibited by prednisolone. Therefore, GC treatment suppresses the up-regulation of the LPS receptor during endotoxin challenge, and likewise, the IL-1 secretion after LPS stimulus was significantly diminished. Taken together, the suppression of the monocytic cell surface and soluble endotoxin receptor CD14 by GC may contribute to the increased risk of infections in patients undergoing steroid therapy.

12

Berthelot, L., P. Housset, V. Sauvaget, A. Jamin, R. C. Monteiro, and E. Pillebout. "Complexes IgA-CD89 soluble comme biomarqueurs d’atteinte rénale et facteur de risque de progression au cours du purpura rhumatoïde." Néphrologie & Thérapeutique 9, no. 5 (September 2013): 278. http://dx.doi.org/10.1016/j.nephro.2013.07.184.

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13

Tissandié, Emilie, Willy Morelle, Laureline Berthelot, François Vrtovsnik, Eric Daugas, Francine Walker, Didier Lebrec, et al. "Both IgA nephropathy and alcoholic cirrhosis feature abnormally glycosylated IgA1 and soluble CD89–IgA and IgG–IgA complexes: common mechanisms for distinct diseases." Kidney International 80, no. 12 (December 2011): 1352–63. http://dx.doi.org/10.1038/ki.2011.276.

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14

Monteiro, Renato C., Dina Rafeh, and Patrick J. Gleeson. "Is There a Role for Gut Microbiome Dysbiosis in IgA Nephropathy?" Microorganisms 10, no. 4 (March 22, 2022): 683. http://dx.doi.org/10.3390/microorganisms10040683.

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Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.

15

Chai, Jian-Guo, Silvia Vendetti, Istvan Bartok, Diana Schoendorf, Katalin Takacs, James Elliott, Robert Lechler, and Julian Dyson. "Critical Role of Costimulation in the Activation of Naive Antigen-Specific TCR Transgenic CD8+ T Cells In Vitro." Journal of Immunology 163, no. 3 (August 1, 1999): 1298–305. http://dx.doi.org/10.4049/jimmunol.163.3.1298.

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Abstract The influence of costimulation on the activation of naive CD8+ T cells and thymocytes was studied in vitro using H-Y-specific TCR-transgenic mice and H-Y antigenic peptide. Using a variety of physiological APC types, the activation of naive CD8+ T cells depended strictly on costimulation, which could not be substituted by high epitope density. T cell activation is known to be regulated by the interactions between CD86/CD80 and CD28/CD152, although it remains unclear whether the B7 isoforms have distinct roles. Addition of soluble anti-CD86 Ab led to profound inhibition of T cell reactivity, further confirming the importance of costimulation in naive CD8+ T cell activation. Finally, TCR engagement in the absence of costimulation had no effect on the subsequent reactivity of peripheral naive transgenic CD8+ T cells, but induced nonresponsiveness in mature CD8+ transgenic thymocytes. Collectively, these results demonstrate the importance of costimulation for naive CD8+ T cell activation, suggest that CD80 and CD86 can mediate opposing effects, possibly due to differential interaction with CD152 and CD28, and indicate differences in the sensitivity of immature vs mature CD8+ T cells to the induction of nonresponsiveness following costimulation-deficient Ag presentation.

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Lal, R. B., D. L. Rudolph, C. S. Dezzutti, P. S. Linsley, and H. E. Prince. "Costimulatory effects of T cell proliferation during infection with human T lymphotropic virus types I and II are mediated through CD80 and CD86 ligands." Journal of Immunology 157, no. 3 (August 1, 1996): 1288–96. http://dx.doi.org/10.4049/jimmunol.157.3.1288.

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Abstract The modulation of expression of CD80 and CD86 on T cells following infection with human T lymphotropic virus (HTLV)-I/II and its functional importance in T-T cell interactions was examined. Infection with HTLV-I/II leads to constitutive expression of CD80 and CD86, concomitant to down-modulation of CD28 on T cells. The CD80/CD86+ HTLV-infected T cells stimulated proliferation of allogeneic and autologous resting T cells, which could be specifically blocked by a soluble CTLA-4Ig chimeric protein, anti-CD80 or anti-CD86, but not by anti-CD54. It was necessary to inhibit interaction with both ligands (CD80 and CD86) to optimally block HTLV-mediated proliferation of allogeneic and autologous resting T cells. Simultaneous addition of anti-CD8O and anti-CD86 Abs also inhibited production of IFN-gamma, TNF-alpha, and IL-4, with no effect on IL-10 production, for both allo- and autologous T cell proliferation. Further, there was a direct correlation between the spontaneous proliferation of lymphocytes from patients infected with HTLV-II and expression of CD80, which could be blocked by simultaneous addition of anti-CD80 and anti-CD86. Taken together, these results suggest that HTLV-infected CD80/CD86+ T cells serve as APCs, leading to a sustained proliferation of T cells, and that both ligands participate in allostimulation, autologous proliferation, as well as spontaneous proliferation of HTLV-II-infected PBMC.

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Motta, Juliana, Morgana Castelo-Branco, and Vivian Rumjanek. "Characterization of human monocyte-derived dendritic cells in the presence of leukemic cell soluble products (127.14)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 127.14. http://dx.doi.org/10.4049/jimmunol.188.supp.127.14.

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Abstract Professional antigen-presenting cells, dendritic cells (DCs) play an important role in controlling tumors, since they are able to initiate an antitumoral immune response. Some works demonstrate that products secreted by solid tumor cells can modulate DCs, however, leukemic cell products are not well studied. Considering that leukemic cells are present in the same place as monocytes (DCs precursor), we analyzed a possible influence of leukemic cell products on DC development and function. For this, monocytes from healthy donors were separated by density gradient and cultured, for 5 days, in the presence of IL-4 and GM-CSF and also with K562 supernatant (SN). In another experiment, immature DCs were cultured with TNF-α for a further 2 days. During a control differentiation, monocytes down regulate CD14, CD16 and CD68 expression and start to express CD1a. In this stage, immature DCs present high endocytic ability. In the presence of SN K562, CD14, CD16 and CD68 expression remained high and CD1a expression was low. However, the addition of SN K562 did not interfere with dextran endocytosis. If activated, DCs increase CD83, CD80 and CD86 expression. It was observed that monocytes differentiated in the presence of SN K562 and then activated expressed less CD83, although CD80 and CD86 expression were not modulated. Finally, these results suggest that products released by leukemic cells affect DC differentiation and these cells become unable to complete their development.

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Chai, Jian-Guo, Istvan Bartok, Diane Scott, Julian Dyson, and Robert Lechler. "T:T Antigen Presentation by Activated Murine CD8+ T Cells Induces Anergy and Apoptosis." Journal of Immunology 160, no. 8 (April 15, 1998): 3655–65. http://dx.doi.org/10.4049/jimmunol.160.8.3655.

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Abstract Using an IL-2-secreting, noncytolytic, H-Y-specific, CD8+ T cell clone, the functional consequences of Ag presentation by T cells to T cells were investigated. Incubation of the T cells with H-Y-soluble peptide led to nonresponsiveness to Ag rechallenge. This was due to the simultaneous induction of apoptosis, involving approximately 40% of the T cells, and of anergy in the surviving cells. These effects were strictly dependent upon bidirectional T:T presentation, in that exposure of C6 cells to peptide-pulsed T cells from the same clone induced proliferation but not apoptosis or anergy. The inhibitory effects of T:T presentation were not due to a lack of costimulation, since the T cells expressed levels of CD80 and CD86 higher than those detected on cultured dendritic cells and equipped them to function as efficient APCs for primary CD8+ T cell responses. Following incubation with soluble peptide, CD80 expression increased, and high levels of CTLA-4 (CD152) expression were induced. Although addition of anti-CTLA-4 Ab augmented proliferation in response to soluble peptide, no protection from apoptosis or anergy was observed. Neither Fas nor TNF-α was expressed/produced by the C6 cells, and coligation of MHC class I molecules and TCR failed to reproduce the effects of T:T presentation. Taken together, these data suggest that T:T Ag presentation induces anergy and apoptosis in murine CD8+ T cells and may reflect the regulatory consequences of T:T interactions in the course of clonal expansion in vivo.

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Chung, Yeonseok, Jae-Hoon Chang, Mi-Na Kweon, Paul D. Rennert, and Chang-Yuil Kang. "CD8α–11b+ dendritic cells but not CD8α+ dendritic cells mediate cross-tolerance toward intestinal antigens." Blood 106, no. 1 (July 1, 2005): 201–6. http://dx.doi.org/10.1182/blood-2004-11-4240.

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Cross-presentation is a critical process by which antigen is displayed to CD8 T cells to induce tolerance. It is believed that CD8α+ dendritic cells (DCs) are responsible for cross-presentation, suggesting that the CD8α+ DC population is capable of inducing both cross-priming and cross-tolerance to antigen. We found that cross-tolerance against intestinal soluble antigen was abrogated in C57BL/6 mice lacking mesenteric lymph nodes (MLNs) and Peyer patches (PPs), whereas mice lacking PPs alone were capable of developing CD8 T-cell tolerance. CD8α–CD11b+ DCs but not CD8α+ DCs in the MLNs present intestinal antigens to relevant CD8 T cells, while CD8α+ DCs but not CD8α–CD11b+ DCs in the spleen exclusively cross-present intravenous soluble antigen. Thus, CD8α–CD11b+ DCs in the MLNs play a critical role for induction of cross-tolerance to dietary proteins.

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Hock, B. D., J. L. O'Donnell, K. Taylor, A. Steinkasserer, J. L. McKenzie, A. G. Rothwell, and K. L. Summers. "Levels of the soluble forms of CD80, CD86, and CD83 are elevated in the synovial fluid of rheumatoid arthritis patients." Tissue Antigens 67, no. 1 (January 2006): 57–60. http://dx.doi.org/10.1111/j.1399-0039.2005.00524.x.

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Morva, Ahsen, Sébastien Lemoine, Achouak Achour, Jacques-Olivier Pers, Pierre Youinou, and Christophe Jamin. "Maturation and function of human dendritic cells are regulated by B lymphocytes." Blood 119, no. 1 (January 5, 2012): 106–14. http://dx.doi.org/10.1182/blood-2011-06-360768.

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Abstract Mature dendritic cells (DCs) are stimulators of T-cell immune response, whereas immature DCs support T-cell tolerance. Murine B cells can inhibit the production of IL-12 by DCs and thereby hinder the inflammatory response. Notwithstanding the importance of this modulation, only a few studies are available in humans. Here, we have developed an in vitro model of cocultures to assess its significance. We establish that human activated B cells restrained the development of monocytes into immature DCs and their differentiation into mature DCs. In addition, they decreased the density of HLA-DR from mature DCs, the expression of CD80 and CD86 coactivation molecules, the production of IL-12p70 required for antigen presentation and Th1 differentiation, and inhibited the DC-induced T-cell proliferation. These modulations were mediated by CD19+IgDlowCD38+CD24lowCD27− B cells and needed direct cell-to-cell contacts that involved CD62L for the control of CD80 and CD86 expression and a soluble factor for the control of IL-12 production. Moreover, mature DCs from patients with systemic lupus erythematosus displayed insensitivity to the regulation of IL-12. Overall, it appears that human B cells can regulate DC maturation and function and that inefficient B-cell regulation may influence an improper balance between an effector inflammatory response and tolerance induction.

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Li, Haiyan, Sungyoul Hong, Jianfei Qian, Yuhuan Zheng, Jing Yang, and Qing Yi. "Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells." Blood 116, no. 2 (July 15, 2010): 210–17. http://dx.doi.org/10.1182/blood-2009-11-255026.

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Abstract The bone and immune systems are closely related through cellular and molecular interactions. Because bone-resorbing osteoclasts (OCs) are derived from the monocyte/macrophage lineage, similar to dendritic cells (DCs), we hypothesized that OCs could serve as antigen-presenting cells (APCs) to activate T cells. In this study, OCs were generated from human monocytes with stimulation by receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Results showed that, similar to DCs, OCs express major histocompatibility complex (MHC) classes I and II, and CD80, CD86, and CD40; and uptake soluble antigens. OCs secrete interleukin-10 (IL-10), transforming growth factor-β (TGF-β), IL-6, and tumor necrosis factor-α (TNF-α), but not IL-12p70. OCs present allogeneic antigens and activate both CD4+ and CD8+ alloreactive T cells in an MHC-restricted fashion. OCs also present soluble protein tetanus toxoid to activate autologous CD4+ T cells. These findings indicate that OCs can function as APCs and activate both CD4+ and CD8+ T cells. Thus, our study provides new insight into the effect of OCs on the immune system and may help develop novel strategies for treating diseases such as rheumatoid arthritis and multiple myeloma, which affect both the bone and immune systems.

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Oehler, Leopold, Otto Majdic, Winfried F. Pickl, Johannes Stöckl, Elisabeth Riedl, Johannes Drach, Klemens Rappersberger, Klaus Geissler, and Walter Knapp. "Neutrophil Granulocyte–committed Cells Can Be Driven to Acquire Dendritic Cell Characteristics." Journal of Experimental Medicine 187, no. 7 (April 6, 1998): 1019–28. http://dx.doi.org/10.1084/jem.187.7.1019.

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Polymorphonuclear granulocytes (PMNs) are thought to fulfill their role in host defense primarily via phagocytosis and release of cytotoxic compounds and to be inefficient in antigen presentation and stimulation of specific T cells. Dendritic cells (DCs), in contrast, are potent antigen-presenting cells with the unique capacity to initiate primary immune responses. We demonstrate here that highly purified lactoferrin-positive immediate precursors of end-stage neutrophilic PMN (PMNp) can be reverted in their functional maturation program and driven to acquire characteristic DC features. Upon culture with the cytokine combination granulocyte/macrophage colony-stimulating factor plus interleukin 4 plus tumor necrosis factor α, they develop DC morphology and acquire molecular features characteristic for DCs. These molecular changes include neo-expression of the DC-associated surface molecules cluster of differentiation (CD)1a, CD1b, CD1c, human leukocyte antigen (HLA)-DR, HLA-DQ, CD80, CD86, CD40, CD54, and CD5, and downregulation of CD15 and CD65s. Additional stimulation with CD40 ligand induces also expression of CD83 and upregulates CD80, CD86, and HLA-DR. The neutrophil-derived DCs are potent T cell stimulators in allogeneic, as well as autologous, mixed lymphocyte reactions (MLRs), whereas freshly isolated neutrophils are completely unable to do so. In addition, neutrophil-derived DCs are at least 10,000 times more efficient in presenting soluble antigen to autologous T cells when compared to freshly isolated monocytes. Also, in functional terms, these neutrophil-derived DCs thus closely resemble “classical” DC populations.

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Tekguc, Murat, James Badger Wing, Motonao Osaki, Jia Long, and Shimon Sakaguchi. "Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells." Proceedings of the National Academy of Sciences 118, no. 30 (July 23, 2021): e2023739118. http://dx.doi.org/10.1073/pnas.2023739118.

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Foxp3-expressing CD4+CD25+ regulatory T cells (Tregs) constitutively and highly express the immune checkpoint receptor cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism of Treg-mediated suppression, Treg-expressed CTLA-4 down-regulates the expression of CD80/CD86 costimulatory molecules on antigen-presenting cells (APCs). Here, we show that Treg-expressed CTLA-4 facilitated Treg-APC conjugation and immune synapse formation. The immune synapses thus formed provided a stable platform whereby Tregs were able to deplete CD80/CD86 molecules on APCs by extracting them via CTLA-4–dependent trogocytosis. The depletion occurred even with Tregs solely expressing a mutant CTLA-4 form lacking the cytoplasmic portion required for its endocytosis. The CTLA-4–dependent trogocytosis of CD80/CD86 also accelerated in vitro and in vivo passive transfer of other membrane proteins and lipid molecules from APCs to Tregs without their significant reduction on the APC surface. Furthermore, CD80 down-regulation or blockade by Treg-expressed membrane CTLA-4 or soluble CTLA-4-immunoglobulin (CTLA-4-Ig), respectively, disrupted cis-CD80/programmed death ligand-1 (PD-L1) heterodimers and increased free PD-L1 on dendritic cells (DCs), expanding a phenotypically distinct population of CD80lo free PD-L1hi DCs. Thus, Tregs are able to inhibit the T cell stimulatory activity of APCs by reducing their CD80/CD86 expression via CTLA-4–dependent trogocytosis. This CD80/CD86 reduction on APCs is able to exert dual suppressive effects on T cell immune responses by limiting CD80/CD86 costimulation to naïve T cells and by increasing free PD-L1 available for the inhibition of programmed death-1 (PD-1)–expressing effector T cells. Blockade of CTLA-4 and PD-1/PD-L1 in combination may therefore synergistically hinder Treg-mediated immune suppression, thereby effectively enhancing immune responses, including tumor immunity.

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Arcaro, Alexandre, Claude Grégoire, Talitha R. Bakker, Lucia Baldi, Martin Jordan, Laurence Goffin, Nicole Boucheron, et al. "CD8β Endows CD8 with Efficient Coreceptor Function by Coupling T Cell Receptor/CD3 to Raft-associated CD8/p56lck Complexes." Journal of Experimental Medicine 194, no. 10 (November 19, 2001): 1485–95. http://dx.doi.org/10.1084/jem.194.10.1485.

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The extraordinary sensitivity of CD8+ T cells to recognize antigen impinges to a large extent on the coreceptor CD8. While several studies have shown that the CD8β chain endows CD8 with efficient coreceptor function, the molecular basis for this is enigmatic. Here we report that cell-associated CD8αβ, but not CD8αα or soluble CD8αβ, substantially increases the avidity of T cell receptor (TCR)-ligand binding. To elucidate how the cytoplasmic and transmembrane portions of CD8β endow CD8 with efficient coreceptor function, we examined T1.4 T cell hybridomas transfected with various CD8β constructs. T1.4 hybridomas recognize a photoreactive Plasmodium berghei circumsporozoite (PbCS) peptide derivative (PbCS (4-azidobezoic acid [ABA])) in the context of H-2Kd, and permit assessment of TCR-ligand binding by TCR photoaffinity labeling. We find that the cytoplasmic portion of CD8β, mainly due to its palmitoylation, mediates partitioning of CD8 in lipid rafts, where it efficiently associates with p56lck. In addition, the cytoplasmic portion of CD8β mediates constitutive association of CD8 with TCR/CD3. The resulting TCR-CD8 adducts exhibit high affinity for major histocompatibility complex (MHC)-peptide. Importantly, because CD8αβ partitions in rafts, its interaction with TCR/CD3 promotes raft association of TCR/CD3. Engagement of these TCR/CD3-CD8/lck adducts by multimeric MHC-peptide induces activation of p56lck in rafts, which in turn phosphorylates CD3 and initiates T cell activation.

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Tsuji, Shoutaro, Misako Matsumoto, Osamu Takeuchi, Shizuo Akira, Ichiro Azuma, Akira Hayashi, Kumao Toyoshima, and Tsukasa Seya. "Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Involvement of Toll-Like Receptors." Infection and Immunity 68, no. 12 (December 1, 2000): 6883–90. http://dx.doi.org/10.1128/iai.68.12.6883-6890.2000.

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ABSTRACT The constituents of mycobacteria are an effective immune adjuvant, as observed with complete Freund's adjuvant. In this study, we demonstrated that the cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guérin (BCG-CWS), a purified noninfectious material consisting of peptidoglycan, arabinogalactan, and mycolic acids, induces maturation of human dendritic cells (DC). Surface expression of CD40, CD80, CD83, and CD86 was increased by BCG-CWS on human immature DC, and the effect was similar to those of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), heat-killed BCG, and viable BCG. BCG-CWS induced the secretion of TNF-α, IL-6, and IL-12 p40. CD83 expression was increased by a soluble factor secreted from BCG-CWS-treated DC and was completely inhibited by monoclonal antibodies against TNF-α. BCG-CWS-treated DC stimulated extensive allogeneic mixed lymphocyte reactions. The level of TNF-α secreted through BCG-CWS was partially suppressed in murine macrophages with no Toll-like receptor 2 (TLR 2) or TLR4 and was completely lost in TLR2 and TLR4 double-deficient macrophages. These results suggest that the BCG-CWS induces TNF-α secretion from DC via TLR2 and TLR4 and that the secreted TNF-α induces the maturation of DC per se.

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Lechmann, Matthias, Daniëlle J. E. B. Krooshoop, Diana Dudziak, Elisabeth Kremmer, Christine Kuhnt, Carl G. Figdor, Gerold Schuler, and Alexander Steinkasserer. "The Extracellular Domain of CD83 Inhibits Dendritic Cell–mediated T Cell Stimulation and Binds to a Ligand on Dendritic Cells." Journal of Experimental Medicine 194, no. 12 (December 17, 2001): 1813–21. http://dx.doi.org/10.1084/jem.194.12.1813.

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CD83 is an immunoglobulin (Ig) superfamily member that is upregulated during the maturation of dendritic cells (DCs). It has been widely used as a marker for mature DCs, but its function is still unknown. To approach its potential functional role, we have expressed the extracellular Ig domain of human CD83 (hCD83ext) as a soluble protein. Using this tool we could show that immature as well as mature DCs bind to CD83. Since CD83 binds a ligand also expressed on immature DCs, which do not express CD83, indicates that binding is not a homophilic interaction. In addition we demonstrate that hCD83ext interferes with DC maturation downmodulating the expression of CD80 and CD83, while no phenotypical effects were observed on T cells. Finally, we show that hCD83ext inhibits DC-dependent allogeneic and peptide-specific T cell proliferation in a concentration dependent manner in vitro. This is the first report regarding functional aspects of CD83 and the binding of CD83 to DCs.

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Nauta, Alma J., Ellie Lurvink, Alwine B. Kruisselbrink, Roelof Willemze, and Willem E. Fibbe. "Mesenchymal Stem Cells Inhibit Generation and Function of Both Monocyte-Derived and CD34-Derived Dendritic Cells." Blood 106, no. 11 (November 16, 2005): 593. http://dx.doi.org/10.1182/blood.v106.11.593.593.

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Abstract Mesenchymal stem cells (MSCs) have been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of MSCs on the differentiation and function of both monocyte-derived DCs and CD34+-derived DCs were investigated. Monocytes (CD1a-CD14+) were obtained from PB and were cultured with IL-4 and GM-CSF to induce differentiation into CD14-CD1a+ immature DCs. CD34+ hematopoietic progenitor cells were isolated from umbilical cord blood samples and cultured in the presence of GM-CSF, TNF-a, and SCF to generate Langerhans cells, which differentiate directly into CD1a+ DCs, and dermal/interstitial DCs, which differentiate via an intermediate CD14+CD1a- phenotype into CD14-CD1a+ DCs. MSCs were generated from fetal lung tissue as reported previously (Exp. Hematol.2002; 30: 870–878). The phenotype (CD1a, CD14, CD80, CD86, CD83, HLA-DR, CD40) of the cells was analyzed by flow cytometry; cytokine production (IL-12, TNF-α) was examined by enzyme-linked immunosorbent assay (ELISA) and T cell stimulatory capacity was determined by a mixed lymphocyte reaction (MLR). The presence of MSCs during the complete differentiation period completely prevented the generation of immature DCs (CD1a+CD14-) from monocytes in a dose-dependent manner. MSCs in the upper wells of a transwell culture system inhibited the differentiation of monocytes in the lower wells, indicating that the suppressive effect of MSCs was mediated via soluble factors. The inhibitory effect of MSCs on the differentiation of DCs was partially prevented by the addition of neutralizing antibodies to IL-6 and M-CSF, indicating the involvement of these cytokines. Upon removal of MSCs cultured in a transwell after 48h, differentiation of monocytes towards DCs was restored, indicating that the suppressive effect of MSCs was reversible. DCs generated in the presence of MSCs were unresponsive to signals inducing maturation (CD40 ligand, lipopolysaccharide), as demonstrated by the absence of CD83, CD80, CD86 and HLA-DR upregulation and the decreased production of the inflammatory cytokines TNF-α (76%) and IL-12 (79%). In addition, the T cell stimulatory capacity of mature DCs generated in the presence of MSCs was strongly reduced. MSCs also inhibited the generation of DCs from CD34+ progenitor cells by blocking the differentiation of CD14+CD1a- precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. The inhibitory effect of MSCs on CD34+ cell differentiation was dose-dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules (CD80, CD86) and CD83, and hampered capacity to stimulate naïve T-cell proliferation (50,112 ± 1,305 cpm versus 20,412 ± 1,593 cpm). Taken together, these data demonstrate that MSCs, next to the anti-proliferative effect on T cells, have a profound inhibitory effect on the generation and function of both monocyte- and CD34+-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.

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Corinti, Silvia, Donata Medaglini, Andrea Cavani, Maria Rescigno, Gianni Pozzi, Paola Ricciardi-Castagnoli, and Giampiero Girolomoni. "Human Dendritic Cells Very Efficiently Present a Heterologous Antigen Expressed on the Surface of Recombinant Gram-Positive Bacteria to CD4+ T Lymphocytes." Journal of Immunology 163, no. 6 (September 15, 1999): 3029–36. http://dx.doi.org/10.4049/jimmunol.163.6.3029.

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Abstract Recombinant Streptococcus gordonii expressing on the surface the C-fragment of tetanus toxin was tested as an Ag delivery system for human monocyte-derived dendritic cells (DCs). DCs incubated with recombinant S. gordonii were much more efficient than DCs pulsed with soluble C-fragment of tetanus toxin at stimulating specific CD4+ T cells as determined by cell proliferation and IFN-γ release. Compared with DCs treated with soluble Ag, DCs fed with recombinant bacteria required 102- to 103-fold less Ag and were at least 102 times more effective on a per-cell basis for activating specific T cells. S. gordonii was internalized in DCs by conventional phagocytosis, and cytochalasin D inhibited presentation of bacteria-associated Ag, but not of soluble Ag, suggesting that phagocytosis was required for proper delivery of recombinant Ag. Bacteria were also very potent inducers of DC maturation, although they enhanced the capacity of DCs to activate specific CD4+ T cells at concentrations that did not stimulate DC maturation. In particular, S. gordonii dose-dependently up-regulated expression of membrane molecules (MHC I and II, CD80, CD86, CD54, CD40, CD83) and reduced both phagocytic and endocytic activities. Furthermore, bacteria promoted in a dose-dependent manner DC release of cytokines (IL-6, TNF-α, IL-1β, IL-12, TGF-β, and IL-10) and of the chemokines IL-8, RANTES, IFN-γ-inducible protein-10, and monokine induced by IFN-γ. Thus, recombinant Gram-positive bacteria appear a powerful tool for vaccine design due to their extremely high capacity to deliver Ags into DCs, as well as induce DC maturation and secretion of T cell chemoattractans.

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Faries, Mark B., Isabelle Bedrosian, Shuwen Xu, Gary Koski, James G. Roros, Mirielle A. Moise, Hung Q. Nguyen, Friederike H. C. Engels, Peter A. Cohen, and Brian J. Czerniecki. "Calcium signaling inhibits interleukin-12 production and activates CD83+ dendritic cells that induce Th2 cell development." Blood 98, no. 8 (October 15, 2001): 2489–97. http://dx.doi.org/10.1182/blood.v98.8.2489.

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Abstract Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-γ, TNF-α, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1β, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1β, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-γ, TNF-α, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.

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Andersson, Anders, Apostolos Bossios, Carina Malmhäll, Margareta Sjöstrand, Maria Eldh, Britt-Marie Eldh, Pernilla Glader, et al. "Effects of tobacco smoke on IL-16 in CD8+ cells from human airways and blood: a key role for oxygen free radicals?" American Journal of Physiology-Lung Cellular and Molecular Physiology 300, no. 1 (January 2011): L43—L55. http://dx.doi.org/10.1152/ajplung.00387.2009.

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Chronic exposure to tobacco smoke leads to an increase in the frequency of infections and in the number of CD8+ and CD4+ cells as well as the CD4+ chemoattractant cytokine IL-16 in the airways. Here, we investigated whether tobacco smoke depletes intracellular IL-16 protein and inhibits de novo production of IL-16 in CD8+ cells from human airways and blood while increasing extracellular IL-16 and whether oxygen free radicals (OFR) are involved. Intracellular IL-16 protein in CD8+ cells and mRNA in all cells was decreased in bronchoalveolar lavage (BAL) samples from chronic smokers. This was also the case in human blood CD8+ cells exposed to water-soluble tobacco smoke components in vitro, in which oxidized proteins were markedly increased. Extracellular IL-16 protein was increased in cell-free BAL fluid from chronic smokers and in human blood CD8+ cells exposed to water-soluble tobacco smoke components in vitro. This was not observed in occasional smokers after short-term exposure to tobacco smoke. A marker of activation (CD69) was slightly increased, whereas other markers of key cellular functions (membrane integrity, apoptosis, and proliferation) in human blood CD8+ cells in vitro were negatively affected by water-soluble tobacco smoke components. An OFR scavenger prevented these effects, whereas a protein synthesis inhibitor, a β-adrenoceptor, a glucocorticoid receptor agonist, a phosphodiesterase, a calcineurin phosphatase, and a caspase-3 inhibitor did not. In conclusion, tobacco smoke depletes preformed intracellular IL-16 protein, inhibits its de novo synthesis, and distorts key cellular functions in human CD8+ cells. OFR may play a key role in this context.

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Zinser, Elisabeth, Matthias Lechmann, Antje Golka, Manfred B. Lutz, and Alexander Steinkasserer. "Prevention and Treatment of Experimental Autoimmune Encephalomyelitis by Soluble CD83." Journal of Experimental Medicine 200, no. 3 (August 2, 2004): 345–51. http://dx.doi.org/10.1084/jem.20030973.

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CD83 is up-regulated on the surface of dendritic cells (DCs) during maturation and has been widely used as a marker for mature DCs. Recently, we reported the recombinant expression of the extracellular immunoglobulin domain of human CD83 (hCD83ext). Using this soluble form of CD83, allogeneic as well as specific cytotoxic T lymphocyte proliferation could be blocked in vitro. Here we report the functional analysis of soluble CD83 in vivo, using murine experimental autoimmune encephalomyelitis (EAE) as a model. Strikingly, only three injections of soluble CD83 prevented the paralysis associated with EAE almost completely. In addition, even when the EAE was induced a second time, CD83-treated mice were protected, indicating a long-lasting suppressive effect. Furthermore, soluble CD83 strongly reduced the paralysis in different therapeutic settings. Most important, even when the treatment was delayed until the disease symptoms were fully established, soluble CD83 clearly reduced the paralyses. In addition, also when EAE was induced a second time, soluble CD83-treated animals showed reduced disease symptoms. Finally, hCD83ext treatment almost completely reduced leukocyte infiltration in the brain and in the spinal cord. In summary, this work strongly supports an immunosuppressive role of soluble CD83, thereby indicating its therapeutic potential in the regulation of immune disorders in vivo.

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Bowman, Christine E., Ada Chen, Damie Juat, Kaustubh Parashar, Julie Clor, Hema Singh, Ritu Kushwaha, et al. "Abstract 321: Inhibition of CD39 results in elevated ATP and activation of myeloid cells to promote anti-tumor immunity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 321. http://dx.doi.org/10.1158/1538-7445.am2022-321.

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Abstract CD39 (ENTPD1) is an ecto-nucleoside triphosphate diphosphohydrolase expressed widely in the tumor microenvironment (TME) responsible for catalyzing the conversion of ATP to AMP. Inhibition of CD39 enzymatic activity can promote anti-tumor immune responses by increasing the immunostimulatory substrate ATP and decreasing the formation of the product AMP, a precursor to immunoinhibitory adenosine. CD39 inhibition has been shown to have an anti-tumor effect by activating dendritic cells, macrophages, and NK cells in the TME to promote antigen presentation and inflammatory cytokine release. AB598 is a novel antibody, highly specific for human and cynomolgus CD39. AB598 potently binds to CD39 expressed on human primary myeloid cells and tumor cells and potently inhibits both soluble and membrane-bound CD39 enzymatic activity. CD39 inhibition results in increased extracellular ATP (eATP) in the TME and subsequent activation of P2X and P2Y receptors. Myeloid cells highly express both CD39 and P2X7, the P2X receptor with the weakest ligand affinity for ATP (greater than 100 μM), and most likely to be specifically activated by very high levels of eATP resulting from CD39 inhibition. Thus, the myeloid compartment has emerged as a key target associated with the therapeutic effects of CD39 inhibition. AB598 retains the ability to bind and inhibit membrane bound CD39 in the presence of high ATP (400 μM). AB598 promotes maturation of human dendritic cells in the presence of ATP, as determined by increased expression of CD83 and CD86 and decreased expression of CD14. In human macrophages treated with ATP, AB598 activates the inflammasome, resulting in the secretion of pro-inflammatory IL-18 and IL-1β. The ATP-dependent effects of AB598 support a therapeutic rationale of combining it with immunogenic therapies that induce release of ATP, such as chemotherapy and radiation, which might represent a new paradigm in the treatment of advanced solid tumors. Citation Format: Christine E. Bowman, Ada Chen, Damie Juat, Kaustubh Parashar, Julie Clor, Hema Singh, Ritu Kushwaha, Bryan Handlos, Suan Liu, Janine Kline, Xiaoning Zhao, Hyock Joo Kwon, David Green, Stephen W. Young, Ester Fernandez-Salas, Matthew J. Walters, Nigel P. Walker. Inhibition of CD39 results in elevated ATP and activation of myeloid cells to promote anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 321.

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Tomita, Yuji, Eri Watanabe, Masumi Shimizu, Yasuyuki Negishi, Yukihiro Kondo, and Hidemi Takahashi. "Induction of tumor-specific CD8+ cytotoxic T lymphocytes from naïve human T cells by using Mycobacterium-derived mycolic acid and lipoarabinomannan-stimulated dendritic cells." Cancer Immunology, Immunotherapy 68, no. 10 (September 17, 2019): 1605–19. http://dx.doi.org/10.1007/s00262-019-02396-8.

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Abstract The main effectors in tumor control are the class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1+CD141+ appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1+CD141+ molecules with a cross-presentation function in humans. Thus, if tolerogenic DCs can be reactivated into immunogenic DCs with sufficient co-stimulatory molecules, tumor-specific CD8+ CTLs can be primed and activated in vivo. In the present study, we converted human tolerogenic CD141+ DCs with enhanced co-stimulatory molecule expression of CD40, CD80, and CD86 through stimulation with non-toxic mycobacterial lipids such as mycolic acid (MA) and lipoarabinomannan (LAM), which synergistically enhanced both co-stimulatory molecule expression and interleukin (IL)-12 secretion by XCR1+CD141+ DCs. Moreover, MA and LAM-stimulated DCs captured tumor antigens and presented tumor epitope(s) in association with class I MHCs and sufficient upregulated co-stimulatory molecules to prime naïve CD3+ T cells to become CD8+ tumor-specific CTLs. Repeat CD141+ DC stimulation with MA and LAM augmented the secretion of IL-12. These findings provide us a new method for altering the tumor environment by converting tolerogenic DCs to immunogenic DCs with MA and LAM from Mycobacterium tuberculosis.

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Simone, Rita, Giampaola Pesce, Princey Antola, Margarita Rumbullaku, Marcello Bagnasco, Nicola Bizzaro, and Daniele Saverino. "The Soluble Form of CTLA-4 from Serum of Patients with Autoimmune Diseases Regulates T-Cell Responses." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/215763.

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Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed that CTLA-4 gene is an important susceptibility locus for autoimmune disorders. Alternatively spliced mRNA generates a soluble form, called sCTLA-4. Whereas low levels of sCTLA-4 are detected in normal human serum, increased/high serum levels are observed in several autoimmune diseases. The biological significance of increased sCTLA-4 serum level is not fully clarified yet. It can be envisaged that sCTLA-4 specifically inhibits the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could contend the binding of the membrane form of CTLA-4 with CD80/CD86, in later activation phase, causing a reduction of inhibitory signalling. We showed that sCTLA-4 from sera of patients with different autoimmune diseases is able to display functional activities on anin vitrosystem acting on the proliferation capability and modulating the secretion of cytokines. We observed a dual effect of sCTLA-4: inhibiting the secretion of IFN-γ, IL-2, IL-7, and IL-13 and activating the secretion of TGF-βand IL-10. This study underlines the role of sCTLA-4 in modulating the immune response and its relevance in autoimmune disease pathogenesis.

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Butler, Marcus O., Osamu Imataki, Yoshihiro Yamashita, Makito Tanaka, Sascha Ansén, Alla Berezovskaya, Matthew I. Milstein, et al. "Human CD4+ T Cells Help CD8+ T Cells Proliferate Ex Vivo by Secreting Both IL-2/IL-21 and Upregulating IL-21R." Blood 116, no. 21 (November 19, 2010): 4284. http://dx.doi.org/10.1182/blood.v116.21.4284.4284.

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Abstract Abstract 4284 While adoptive T cell therapy is a promising treatment modality for cancer, the optimal approach to generate T cell grafts ex vivo is currently unknown. CD4+ T cells help generate effective immune responses by sustaining CD8+ T cell proliferation, preventing exhaustion, and establishing long-lived functional memory. Incorporation of CD4+ T cell help to expand CD8+ T cells may provide a novel strategy to generate CTL grafts for adoptive therapy. In mouse models, common γ-chain receptor cytokines and CD40/CD40L can mediate CD4+ T cell help. However, CD4+ T cell help in humans has yet to be fully defined. We therefore developed an in vitro model for human CD4+ T cell help, which utilizes a novel artificial APC, aAPC/mOKT3. K562-based aAPC/mOKT3 expresses a membranous form of anti-CD3 mAb, CD54, CD58, CD80, and CD83 and stimulates CD3+ T cells regardless of HLA haplotype or antigen specificity. Using aAPC/mOKT3, we stimulated CD8+ T cells in the presence or absence of CD4+ T cells and found that CD8+ T cells expanded better when coincubated with CD4+ T cells, suggesting the presence of CD4+ T cell help. Coculture experiments using transwell plates suggested that the observed CD4+ T cell help of CD8+ T cell expansion involved both soluble factors and cell-cell contact. To identify molecules mediating the observed CD4+ T cell help, supernatants of CD4+/CD8+ T cell mixed and separate cultures were measured for a panel of soluble factors. IL-2 and IL-21 were detected at lower levels in mixed cultures, consistent with more consumption or less production of these cytokines. Blockade of either IL-2 or IL-21 in CD4+/CD8+ T cell mixed cultures resulted in a reduction of CD8+ T cell expansion, indicating that, for both cytokines, more consumption rather than less production occurred and that IL-2 and IL-21 may serve as mediators of CD4+ T cell help. However, the addition of IL-21 to CD8+ T cells stimulated with aAPC/mOKT3 in the presence of IL-2 did not improve CD8+ T cell expansion, suggesting that IL-2 plus IL-21 cannot solely replace CD4+ T cell help. We found that the presence of CD4+ T cells upregulated the expression of IL-21R on CD8+ T cells. When we introduced IL-21R on CD8+ T cells and stimulated with aAPC/mOKT3 in the presence of IL-2 and IL-21, CD8+ T cell proliferation was restored. These results suggest that CD4+ T cells help CD8+ T cells proliferate ex vivo by secreting both IL-2/IL-21 and upregulating IL-21R. When peripheral CD3+ T cells from normal donors were stimulated with aAPC/mOKT3, the number of both CD4+ and CD8+ T cells increased. However, in contrast to other pan T cell expansion systems, aAPC/mOKT3 preferentially expanded CD8+ T cells. No obvious skewing in the Vβ usage of both CD4+ and CD8+ T cell populations was revealed by TCR Vβ repertoire analysis, supporting “unbiased” T cell expansion by aAPC/mOKT3. Moreover, HLA-restricted antigen-specific CD8+ CTL with high functional avidity could be generated from CD3+ T cells initially expanded for 4 weeks using aAPC/mOKT3. Using aAPC/mOKT3, tumor-infiltrating lymphocytes (TIL) were successfully expanded without adding soluble mAb or allogeneic feeder cells. As in peripheral T cell cultures, CD8+ T cells predominantly expanded in all cultures, including those that initially contained a minimal percentage of CD8+ T cells. Importantly, Foxp3+ Treg cells did not proliferate. Expanded T cells highly expressed CD27 and CD28, which are associated with T cell survival and persistence in vivo. They also secreted high levels of IFN-γ and IL-2, lower amounts of IL-4, and no IL-10. These results demonstrate that the aAPC/mOKT3-based system can expand functional CD8+ TIL in the presence of autologous CD4+ T cells. In conclusion, we have determined that CD4+ T cell-dependent CD8+ T cell expansion required both soluble factors secreted by and cell contact with CD4+ T cells. Among the soluble factors secreted by CD4+ T cells, IL-2 and IL-21 were necessary. Furthermore, upregulation of IL-21R on CD8+ T cells by CD4+ T cells was critical for an optimized response to IL-21. Thus, in humans, CD4+ T cells help CD8+ T cells proliferate by secreting IL-2/IL-21 and upregulating IL-21R. Our aAPC enabled expansion of CD8+ TIL in the presence of CD4+ T cell help without using soluble mAb or allogeneic feeder cells. Taken together, these results demonstrate the indispensable role of CD4+ T cell help on expanding CD8+ T cells and suggest a novel strategy to generate anti-tumor T cells ex vivo for adoptive therapy. Disclosures: No relevant conflicts of interest to declare.

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Prazma, Charlene M., and Thomas F. Tedder. "Ag-engaged B cells express CD83, a sensitive marker for B cell activation (83.15)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S114. http://dx.doi.org/10.4049/jimmunol.178.supp.83.15.

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Abstract CD83 is predominantly known as a surface marker that defines mature DCs. The generation of CD83−/− mice further demonstrates that thymic epithelial expression of CD83 plays a significant role in the efficient generation of CD4 single positive thymocytes. The altered phenotype and reduced number of peripheral CD4+ T cells in CD83−/− mice further suggests a role for CD83 in the peripheral lymphocyte function. With regards to the surface expression pattern of CD83, CD83 was detected in the thymic medullary compartment and was specifically detected on thymic DCs and B cells in the mouse. Peripheral CD83 expression is limited to low level expression by resting follicular B cells but is quickly upregulated and transiently expressed on nearly 90% of spleen B220+ cells within 4 h of in vivo stimulation. Additionally, the majority (> 70%) of adoptively transferred B cells, expressing a BCR specific to hen egg lysozyme (HEL), expressed CD83 within 4 h of administration of a low dose of soluble HEL. At this timepoint, and low dose of antigen, less than 20% of B220+ splenocytes expressed CD69. Thus, the restricted expression pattern of CD83 and its near immediate upregulation on B cells in response to various stimuli suggest that CD83 is a sensitive, early activation marker of B cells.

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Paul, Santanu, Charles C. Chu, Brian A. McCarthy, Erin Boyle, Bettie M. Steinberg, Matthew Kaufman, Jonathan Kolitz, Steven L. Allen, Kanti R. Rai, and Nicholas Chiorazzi. "Activation of Nucleic Acid-Sensing Toll-Like Receptors Induces Proliferation, Cytokine Production, Immunogenic Phenotype, and Plasma Cell Differentiation of CLL Cells and Immunoglobulin Production." Blood 110, no. 11 (November 16, 2007): 1137. http://dx.doi.org/10.1182/blood.v110.11.1137.1137.

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Abstract Weak immune function of chronic lymphocytic leukemia (CLL) cells may contribute to disease progression and inhibit effective immunotherapy. Accordingly, agents that enhance the function of CLL cells may be useful in immunotherapeutic approaches to this disease. Since Toll-like receptors (TLRs) are major regulators of B-cell function in innate and adaptive immunity, we asked to what extent stimulating two nucleic acid-sensing TLRs affected the activation and differentiation of CLL B cells. Isolated CLL cells were treated with either the TLR7-activating ligand, gardiquimod, or the TLR9-activating ligand ODN 2006-G5. CLL cells were also treated with the contents of apoptotic leukemic B cells, produced by repeated freezing and thawing. Ability to induce proliferation, as defined by CFSE dilution studies, cytokine production, differentiation, and altered surface molecule expression was measured. Both TLR 7 and TLR 9 ligands individually induced high levels of proliferation and plasma cell differentiation of CLL B cells. A dramatic increase in percentage of dividing cells was seen with simultaneous TLR7 and TLR9 activation, while blocking the TLR 7/9 pathway by pre-treating CLL B cells with chloroquine or bafilomycin reduced the proliferative capacity by 90%. Furthermore, stimulating CLL B cells with TLR7 and 9 ligands significantly up-regulated activation (CD38, CD69 and CD83), adhesion (CD54), and other immunophenotypic (CD40, CD80 and CD86) markers. Enzyme immunoassays of culture supernatants after TLR 7 and TLR 9 stimulation indicated that the levels of soluble IgM increased considerably, although levels of cytoplasmic IgM were unchanged. Production of IL6 and IL10 was also induced. We propose that ligands for TLRs 9 and 7 stimulate CLL B cells to proliferate and differentiate into plasma cells in the absence of T-cell help. In addition these stimuli alter CLL cell surface phenotype to a more immunogenetic profile, providing a rationale for CpG oligonucleotides and gardiquimod as humoral vaccine adjuvants for both normal immune reactions and potentially for anti-leukemic therapy.

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Bjørge, Line, Tone Skeie Jensen, Christian A. Vedeler, Elling Ulvestad, Einar K. Kristoffersen, and Roald Matre. "Soluble CD59 in pregnancy and infancy." Immunology Letters 36, no. 2 (May 1993): 233. http://dx.doi.org/10.1016/0165-2478(93)90058-a.

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Paszkiet, Brian, Andrew Worden, Yajin Ni, Saran Bao, Franck Lemiale, Boro Dropulic, and Laurent Humeau. "CD86 and CD54 Co-Expression on VSV-G Pseudotyped HIV-1 Based Vectors Improves Transduction and Activation of Human Primary CD4+ T Lymphocytes." Blood 104, no. 11 (November 16, 2004): 1754. http://dx.doi.org/10.1182/blood.v104.11.1754.1754.

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Abstract We established the first clinical ex vivo HIV-based vector gene therapy trial in humans with HIV+ CD4+ T-cells. Briefly, this therapy involves modifying patient CD4+ T-cells with our modified lentiviral vector carrying an anti-HIV payload. These cells are then activated and expanded, and re-infused back into the patient. However, cGMP regulations require the use of costly clinical grade reagents (i.e. Retronectin™, CD3/CD28 stimulating paramagnetic beads). In an attempt to reduce ex-vivo processing costs, but not at the expense of transduction levels, we sought to determine a way to directly activate CD4+ T-cells with modified lentiviral vectors. 293FT HEK cell lines, used for producing our lentiviral vectors, were modified to co-express the natural CD28 stimulatory ligand B7.2 (CD86) and ICAM-1 (CD54) proteins on their membrane for co-stimulation and anchoring purposes. When CliniMACS purified normal donor CD4+ T cells were co-cultured with CD54/CD86-expressing cells, in the presence of soluble OKT3 CD3 antibody, CD25 and CD69 activation markers were upregulated, indicating that functional proteins were being expressed at the cell membrane. These CD54 and/or CD86 expressing cells could subsequently be transfected with lentiviral vector plasmid constructs in order to produce host-derived CD54 and/or CD86 bearing HIV-based vectors. EGFP-expressing lentiviral vectors, VRX494, with CD54/CD86-modified envelopes were produced both in these cell lines and by transient transfection of all relevant plasmids, and titers were assayed on Hela-Tat cells by FACS. CD54 modified lentiviral vectors showed increased binding to CD4+ T-cells, as evidenced by significant cell clumping. CD86 (as well as CD54 plus CD86) modified lentiviral vector, with soluble OKT3 CD3 antibody, was shown to activate T-cells, above the levels seen with unmodified lentiviral vectors, as evidenced by the increase in cell surface CD25 and CD69 expression and also the increase in cell size. Cellular expansion of modified lentiviral vector transduced CD4+ T cells reached levels close to CD3:CD28 bead stimulated CD4+ T cell controls over a period of 2 to 3 weeks. The CD3/TCR repertoire was assessed by flow cytometry and, compared to the well-established CD3/CD28 coated M450 Dynabeads stimulatory system as a control, no skewing of the repertoire was observed. CD86 was shown to improve levels of transduction in pre-activated lymphocytes with CD3/CD28 coated M450 Dynabeads. However, CD86 co-expression was crucial for transducing minimally activated CD4+ T cells with only soluble OKT3 CD3 antibody. Levels of transduction and activation were on average 2 to 3 times higher with the modified lentiviral vectors. To our knowledge, we are reporting the first generation of lentiviral particles exhibiting an adhesion property with stimulatory abilities. The development of such a lentiviral vector has valuable implications for clinical application by reducing the number of exogenous reagents in large scale cell processing.

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Zelek, Wioleta, Loek Willems, Ricardo Brandwijk, Sam Loveless, Neil R. Robertson, and B. Paul Morgan. "High levels of soluble CD59 in CSF compared to plasma suggests intrathecal source of soluble CD59." Molecular Immunology 89 (September 2017): 186. http://dx.doi.org/10.1016/j.molimm.2017.06.179.

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Zhu, Lv-yun, Li Nie, Tong Shao, Wei-ren Dong, Li-xin Xiang, and Jian-zhong Shao. "B cells in primitive vertebrate act as pivotal antigen presenting cells in priming adaptive immunity (P5035)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 110.18. http://dx.doi.org/10.4049/jimmunol.190.supp.110.18.

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Abstract The long-held paradigm that B cells are unable to phagocyte large particles has been broken by a new discovery that teleost B cells have potent phagocytic and microbicidal abilities. This finding provides preliminary clues that B cells in primitive vertebrates might act as pivotal antigen presenting cells (APCs) in priming adaptive immunity. In this study, we provide evidence for this suggestion in zebrafish model. By in vitro antigen presentation and in vivo adoptive transfer assays, we found that zebrafish B cells have potent capacity to present both soluble and particulate antigens to prime naive CD4+ T cells. The CD86 and CD83 co-stimulatory molecules were identified to be essential for this process. Besides, IL-4 was found to be able to dramatically promote the B cell-mediated CD4+ T cell priming by up-regulating the expression of CD86, CD83 and MHC II molecules on B cells. Our results suggest that B cells in primitive vertebrates were important professional APCs for the initiation of adaptive immunity, whose functional characterization resembles the dendritic cells (DCs). The CD86 and CD83 were two ancient co-stimulatory molecules originating from teleost fish, whose regulatory functions were conserved from fish to mammals throughout vertebrate evolution. These results benefit to the better understanding of the evolutionary history of B subsets such as the origin of B1 cells, as well as the origin of immune-regulatory signaling networks in adaptive immunity.

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Stachel, Daniel K., Uta Eickelmann, Rita Meilbeck, Michael H. Albert, Raymund Buhmann, Michael Hallek, and Irene Schmid. "Coculture of Pediatric Acute Lymphoblastic Leukemia (ALL) Blasts with CD40 Ligand Transfected Cells Leads to Changes of Surface Antigens and RNA Expression." Blood 106, no. 11 (November 16, 2005): 856. http://dx.doi.org/10.1182/blood.v106.11.856.856.

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Abstract Although multi-agent chemotherapy is remarkably successful in the treatment of pediatric acute lymphoblastic leukemia (ALL), about 25% of patients experience relapse. A possible way to increase the cure rate for leukemia could be to modulate the immune response against leukemic cells. It is known that ALL blasts are poor stimulators of cellular immune responses. This is believed to be mainly the result of a reduced presentation of costimulatory molecules on the surface of the ALL blasts. For B cells, CD40 is an essential molecule which can be targeted therapeutically through its ligand, CD40 ligand or CD152. Normal B cells can induce cytotoxic T cell responses following stimulation with a soluble trimeric CD40 ligand. We therefore hypothesized that by coculture with CD40 ligand transfected HeLa cells for four days, pediatric ALL blasts could be induced to upregulate costimulatory molecules, apoptosis inducing ligands and cytokines. The expression of the surface antigens CD40, CD40 ligand, CD80, CD86, CD95/fas, HLA-ABC and HLA-DR was evaluated by flow cytometry and the RNA expression of CD40, CD80, CD86, Fas ligand (FasL), TRAIL, IL-4, IL-6, IL-10, TGF-β was assessed by semiquantitative RT-PCR. We found that coculture with CD40 ligand transfected HeLa cells significantly increased the expression of CD40 ligand, CD80, CD86 and CD95/fas while the expression of HLA-ABC, HLA-DR and CD40 remained unchanged. We found a significantly increased RNA expression of IL-6, TGF-β and CD80, a small but not significant increase of CD86, but no change in expression for IL-4, IL-10, FasL, TRAIL and CD40 after coculture. Addition of IL-4 to the culture did not influence the results. In summary CD40 ligand mediated stimulation lead to increased expression of costimulatory molecules CD80 and CD86 and the pro-apoptotic CD95/fas, while the anti-apoptotic cytokines IL-6 and TGF-β were also upregulated. Our results show that stimulation through CD40 ligation upregulates costimulatory molecules on pediatric ALL blasts, while it has differential effects on apoptosis inducers. This might have functional consequences which could be therapeutically exploited to modulate the immune system in an attempt to increase cure rates in pediatric ALL.

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van der Merwe, P. Anton, Dale L. Bodian, Susan Daenke, Peter Linsley, and Simon J. Davis. "CD80 (B7-1) Binds Both CD28 and CTLA-4 with a Low Affinity and Very Fast Kinetics." Journal of Experimental Medicine 185, no. 3 (February 3, 1997): 393–404. http://dx.doi.org/10.1084/jem.185.3.393.

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The structurally related T cell surface molecules CD28 and CTLA-4 interact with cell surface ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APC) and modulate T cell antigen recognition. Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd values ∼12 and ∼200 nM, respectively) that are high when compared with other molecular interactions that contribute to T cell–APC recognition. In the present study, we use surface plasmon resonance to measure the affinity and kinetics of CD80 binding to CD28 and CTLA-4. At 37°C, soluble recombinant CD80 bound to CTLA-4 and CD28 with Kd values of 0.42 and 4 μM, respectively. Kinetic analysis indicated that these low affinities were the result of very fast dissociation rate constants (koff); sCD80 dissociated from CD28 and CTLA-4 with koff values of ⩾1.6 and ⩾0.43 s−1, respectively. Such rapid binding kinetics have also been reported for the T cell adhesion molecule CD2 and may be necessary to accommodate dynamic T cell–APC contacts and to facilitate scanning of APC for antigen.

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Tomkinson, B. E., M. C. Brown, S. H. Ip, S. Carrabis, and J. L. Sullivan. "Soluble CD8 during T cell activation." Journal of Immunology 142, no. 7 (April 1, 1989): 2230–36. http://dx.doi.org/10.4049/jimmunol.142.7.2230.

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Abstract The CD8 Ag has long been used as a surface marker for the identification of cytotoxic and suppressor cells. Recently CD8-positive cells have been shown to release a soluble form of the CD8 Ag. We have devised a sandwich monoclonal enzyme immunoassay for the quantitation of this released CD8. Soluble CD8 was released in response to lymphocyte activation. In vitro, PHA or anti-CD3 mAb-mediated T cell activation led to release of CD8 into the culture supernatant. In vivo, serum from patients with EBV-induced infectious mononucleosis (IM), a disease associated with intense CD8+ T cell activation, demonstrated elevations in soluble CD8 (7939 U/ml, day 0) compared to serum from normal controls (289 U/ml). Levels of soluble CD8 correlated (r = 0.82, p less than 0.001) with the increased percentage of CD8+/HLA-DR+ (activated CD8+ T cells) observed in acute IM. Sequential analysis of serum during the course of IM shows that soluble CD8 levels parallel the decline in CD8+/HLA-DR+ cells that occurs with the resolution of the disease. These data suggest that released CD8 may be of value in monitoring the involvement of CD8+ T cells in response to a pathologic event. The functional role of the released CD8 molecule will require further investigation.

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Zelek, Wioleta M., Lewis M. Watkins, Owain W. Howell, Rhian Evans, Sam Loveless, Neil P. Robertson, Marijke Beenes, Loek Willems, Ricardo Brandwijk, and B. Paul Morgan. "Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59." Multiple Sclerosis Journal 25, no. 4 (February 9, 2018): 523–31. http://dx.doi.org/10.1177/1352458518758927.

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Background: CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). Objectives: We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. Methods: sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. Results: CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. Conclusion: CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source.

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Nair, Jayakumar R., Louise M. Carlson, Cheryl Rozanski, Lawrence H. Boise, Asher Chanan-Khan, and Kelvin P. Lee. "Direct interaction with dendritic cells through CD28-CD80/CD86 supports plasma cell survival (34.9)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 34.9. http://dx.doi.org/10.4049/jimmunol.182.supp.34.9.

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Abstract The long term survival of plasma cells in their bone marrow niches, necessary to maintain persistent antibody titres, depends on specific survival signals that are produced by their interaction with bone marrow stromal cells (BMSC), interactions that remain largely uncharacterized. Both normal and malignant plasma cells (like myeloma cells) express the T-cell co-stimulatory molecule CD28 and are also known to interact with dendritic cells (DC) in bone marrow biopsies. We also know that ligating CD80/CD86 on DCs with soluble CD28/CTLA4 ligands can up-regulate IL-6, an essential plasma cell survival factor. In our studies, co-culturing CD28+ plasma cells (myeloma cell lines or primary plasma cell isolates) with immature DCs significantly up-regulated DC production of IL-6 (400 - 500 pg/ml as opposed to 40 - 70 pg/ml), which was blocked with anti-CD28 antibodies. Cell-free plasma cell-DC co-culture supernatants supported plasma cell proliferation and survival. Furthermore, plasma cell CD28 binding to CD80/CD86 on DCs induces DC expression and activity of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), which inhibits T cell activation by depleting the essential amino acid tryptophan from the microenvironment. Our study suggests a pro-survival role for DC in regulating plasma cell survival by modulating their bone marrow micro-environment

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Wong, C. K., L. C. W. Lit, L. S. Tam, E. K. Li, and C. W. K. Lam. "Aberrant production of soluble costimulatory molecules CTLA-4, CD28, CD80 and CD86 in patients with systemic lupus erythematosus." Rheumatology 44, no. 8 (May 3, 2005): 989–94. http://dx.doi.org/10.1093/rheumatology/keh663.

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49

Butler, Marcus O., Sascha Ansén, Makito Tanaka, Osamu Imataki, Alla Berezovskaya, Mary M. Mooney, Genita Metzler, Matthew I. Milstein, Lee M. Nadler, and Naoto Hirano. "A Series of Human Cell-Based Artificial APC Expands Long-Lived, Th1-Biased, Viral Antigen-Specific CD4+ T Cells with a Central/Effector Memory Phenotpype Restricted by Common HLA-DR Alleles." Blood 116, no. 21 (November 19, 2010): 354. http://dx.doi.org/10.1182/blood.v116.21.354.354.

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Abstract Abstract 354 Adoptive cell therapy utilizes unique mechanisms of action to prevent the development of infections in immunocompromised patients and treat chemotherapy resistant malignancies. In adoptive cell therapy, the major effector cells appear to be CD8+ T cells, since they are armed with antigen-specific effector functions, i.e. cytotoxicity and cytokine secretion. However, the roles of antigen-specific CD4+ T cells in T cell immunity are also critical. In immunocompromised patients adoptively transferred with CMV-specific CD8+ T cells, long-term in vivo persistence was achieved only when CMV-specific CD4+ T cells were also present in vivo. Recently, adoptive transfer of a NY-ESO-1 specific CD4+ T cell clone was reported to induce a complete response in a patient with metastatic melanoma. These results suggest that adoptive cell therapy for infectious diseases and cancer can be improved by infusing both antigen-specific CD4+ helper T cells as well as CD8+ CTL. Unfortunately, however, few versatile systems are available for producing large numbers of antigen-specific human CD4+ T cells for the purpose of adoptive therapy. K562 is a human erythroleukemic cell line, which lacks the expression of HLA class I and II, invariant chain (Ii), and HLA-DM, but does express adhesion molecules such as ICAM-1 and LFA-3. Given this unique immunologic phenotype, K562 has served as a useful tool in clinical cancer immunotherapy trials. Previously, we reported the generation of a K562-based artificial APC (aAPC), which expresses HLA-A2, CD80, and CD83. aAPC/A2 can uniquely support the priming and prolonged expansion of large numbers of antigen-specific CD8+ CTL which display a central/effector memory phenotype, possess potent effector function, and can be maintained in vitro without any feeder cells or cloning. aAPC/A2 is equipped with constitutive proteasome and inducible immunoproteasome machinery and can naturally process and present CD8+ T cell peptides via transduced A2 molecules. We have successfully generated clinical grade aAPC/A2 under cGMP conditions and conducted a clinical trial where patient with advanced melanoma are infused with large numbers of MART1-specific CTL generated ex vivo using aAPC/A2, IL-2 and IL-15. Based on our experience with aAPC/A2 and CD8+ T cells, we have generated a series of novel aAPC (aAPC/DR1, DR3, DR4, DR7, DR10, DR11, DR13, and DR15) to stimulate HLA-DR-restricted antigen-specific CD4+ T cells. K562 has been engineered to express HLA-DRα and β chains as a single HLA allele in conjunction with Ii, HLA-DMα and β chains, CD80 and CD83. CD83 delivers a CD80-dependent T cell stimulatory signal that allows T cells to be long-lived. Following the transduction of Ii, CLIP (class II invariant chain-associated peptide) appeared on the cell surface of aAPC. Furthermore, CLIP expression on aAPC was almost completely abrogated by the introduction of HLA-DM. This result is in accordance with previous studies showing that HLA-DM catalyzes the removal of CLIP from DR thus enabling exogenous peptides to bind to empty DR molecules in late endosomes. In addition to its endogenous pinocytic activity, aAPC was made capable of Fcγ receptor-mediated endocytosis by transduction of CD64. Comparison of naïve aAPC and CD64-transduced aAPC confirmed that Fcγ receptor-mediated endocytosis is more efficient than pinocytosis to take up soluble protein and process and present DR-restricted peptides to CD4+ T cells. Using these standardized and renewable aAPC, we determined novel viral protein-derived DR-restricted CD4+ T cell epitopes and expanded large numbers of viral antigen-specific CD4+ T cells without growing bystander Foxp3+ regulatory T cells. Without any feeder cells or cloning, expansion of CD4+ T cells using aAPC and low dose IL-2 and IL-15 was sustainable up to 150 days. Immunophenotypic analysis using HLA-DR tetramers and specific mAbs revealed that expanded CD4+ T cells were CD45RA−, CD45RO+, CD62L+-, demonstrating a central/effector memory phenotype. Furthermore, intracellular cytokine analysis showed that expanded DR-restricted viral-specific CD4+ T cells secreted IL-2 and IFN-γ but much less IL-4, displaying a Th1-biased phenotype. Taken all together, these results suggest that K562-based aAPC may serve as a translatable platform to generate both antigen-specific CD4+ helper T cells and CD8+ CTL. Disclosures: No relevant conflicts of interest to declare.

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Eckhardt, J., S. Kreiser, M. Döbbeler, C. Nicolette, M. A. DeBenedette, I. Y. Tcherepanova, C. Ostalecki, et al. "Soluble CD83 ameliorates experimental colitis in mice." Mucosal Immunology 7, no. 4 (January 15, 2014): 1006–18. http://dx.doi.org/10.1038/mi.2013.119.

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Journal articles on the topic 'Soluble CD89'

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