Journal articles: 'T cell activation/tolerance'

1

Priyadharshini, Bhavana, Dale L. Greiner, and Michael A. Brehm. "T-cell activation and transplantation tolerance." Transplantation Reviews 26, no. 3 (July 2012): 212–22. http://dx.doi.org/10.1016/j.trre.2011.09.002.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Phillips, J. A., C. G. Romball, M. V. Hobbs, D. N. Ernst, L. Shultz, and W. O. Weigle. "CD4+ T cell activation and tolerance induction in B cell knockout mice." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1339–44. http://dx.doi.org/10.1084/jem.183.4.1339.

Full text

Abstract:

B cell knockout mice microMT/microMT were used to examine the requirement for B cell antigen (Ag) presentation in the establishment of CD4+ T cell tolerance. CD4+T cells from microMT mice injected with exogenous protein Ag in adjuvant responded to in vitro challenge by transcription of cytokine mRNA, cytokine secretion, and proliferation. Peripheral tolerance could be established in microMT mice with a single dose of deaggragated protein. This tolerance was manifested by a loss of T cell proliferation and cytokine production (including both T helper cell type 1 [Th1]- and Th2-related cytokines), indicating that B cells are not required for the induction of peripheral T cell tolerance and suggesting that the dual zone tolerance theory is not applicable to all protein Ags and is not mediated through Ag presentation by B cells.

APA, Harvard, Vancouver, ISO, and other styles

3

Jonuleit, Helmut, Edgar Schmitt, Hacer Kakirman, Michael Stassen, Jürgen Knop, and Alexander H. Enk. "Infectious Tolerance." Journal of Experimental Medicine 196, no. 2 (July 15, 2002): 255–60. http://dx.doi.org/10.1084/jem.20020394.

Full text

Abstract:

Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression.

APA, Harvard, Vancouver, ISO, and other styles

4

Dowling, Samuel Dae, Enric Mocholi, Ross Gruber, Bridget Shafit-Zagardo, and Fernando Macian. "Macroautophagy regulates T helper cell activation and tolerance." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 56.10. http://dx.doi.org/10.4049/jimmunol.196.supp.56.10.

Full text

Abstract:

Abstract Macroautophagy is a catabolic process whereby cell components, which range from soluble proteins to whole organelles, are sequestered in de novo formed double-membrane autophagosomes that fuse with lysosomes to degrade their cargo. Effector T helper cells induce macroautophagy during activation to maintain cell proliferation and cytokine production. T cells that are unable to upregulate macroautophagy activity show a reduction in ATP generation, suggesting that macroautophagy is necessary to maintain the energy metabolism required to meet the demands of T cell activation. It is presently unknown whether macroautophagy regulates the activation state and functional capacity of CD4+T cells. We explored the instructive role of macroautophagy in effector T helper cell activation and tolerance. Inhibition of macroautophagy during activation of CD4+T helper type 1 (TH1) cells induces a long-lasting state of hyporesponsiveness, with a molecular signature that resembles that of anergic T cells. Moreover, inhibition of macroautophagy prevented activated TH1 cells from upregulating glycolysis and mitochondrial respiration, supporting that macroautophagy may regulate metabolic homeostasis during activation of effector T helper cells. Consequently, inhibition of macroautophagy in vivo prevents CD4+ T cell activation in response to immunization and results in decreased severity of experimental autoimmune encephalomyelitis. Our data support that macroautophagy, likely by regulating metabolism, is necessary for the activation of effector T helper cells and that its absence induces a tolerant state.

APA, Harvard, Vancouver, ISO, and other styles

5

Abbas, Abul K. "The control of T cell activation vs. tolerance." Autoimmunity Reviews 2, no. 3 (May 2003): 115–18. http://dx.doi.org/10.1016/s1568-9972(03)00028-4.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Mondino, A., A. Khoruts, and M. K. Jenkins. "The anatomy of T-cell activation and tolerance." Proceedings of the National Academy of Sciences 93, no. 6 (March 19, 1996): 2245–52. http://dx.doi.org/10.1073/pnas.93.6.2245.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Nurieva, Roza, Guillermina Lozano, and Chen Dong. "Regulation of naïve T cell tolerance and regulatory T cell function by GRAIL (113.21)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 113.21. http://dx.doi.org/10.4049/jimmunol.186.supp.113.21.

Full text

Abstract:

Abstract CD4+ T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self tolerance in CD4+ cells. Gene related to anergy in lymphocytes (GRAIL), the E3 ubiqutine ligase, has acknowledged as one of key molecules implicated in T cell activation and tolerance. In order to understand the physiological function of GRAIL in immune regulation, we have generated and analyzed GRAIL deficient mice. Naive T cells lacking GRAIL showed greatly enhanced proliferation and cytokine production after T cell receptor (TcR) activation. In addition, lack of GRAIL abrogated suppressive function of regulatory T (Treg) cells. We found that GRAIL deficient naive and Treg cells after TcR activation expressed substantially higher amounts of NFATc1 compared to wild-type cells, whereas the activation of other factors in AP-1 and NFκB pathways were normal. Our data also suggested that sustained TcR cell-surface expression in the absence of GRAIL led to selective NFATc1 expression in both naive T cells and Treg cells. In contrast to naïve T cells, GRAIL, through controlling NFATc1 expression, inhibits IL-21 production and upregulation of Th17-specific genes in Treg cells. Thus, the immune regulation by GRAIL in both naive and Treg cells is absolutely critical as evidenced by the failure of T cell tolerance induction and greatly increased susceptibility to autoimmune diseases of GRAIL deficient mice.

APA, Harvard, Vancouver, ISO, and other styles

8

Berg-Brown, Nancy N., Matthew A. Gronski, Russell G. Jones, Alisha R. Elford, Elissa K. Deenick, Bernhard Odermatt, Dan R. Littman, and Pamela S. Ohashi. "PKCθ Signals Activation versus Tolerance In Vivo." Journal of Experimental Medicine 199, no. 6 (March 15, 2004): 743–52. http://dx.doi.org/10.1084/jem.20031022.

Full text

Abstract:

Understanding the pathways that signal T cell tolerance versus activation is key to regulating immunity. Previous studies have linked CD28 and protein kinase C-θ (PKCθ) as a potential signaling pathway that influences T cell activation. Therefore, we have compared the responses of T cells deficient for CD28 and PKCθ in vivo and in vitro. Here, we demonstrate that the absence of PKCθ leads to the induction of T cell anergy, with a phenotype that is comparable to the absence of CD28. Further experiments examined whether PKCθ triggered other CD28-dependent responses. Our data show that CD4 T cell–B cell cooperation is dependent on CD28 but not PKCθ, whereas CD28 costimulatory signals that augment proliferation can be uncoupled from signals that regulate anergy. Therefore, PKCθ relays a defined subset of CD28 signals during T cell activation and is critical for the induction of activation versus tolerance in vivo.

APA, Harvard, Vancouver, ISO, and other styles

9

Lechler, Robert, Jian-Guo Chai, Federica Marelli-Berg, and Giovanna Lombardi. "T–cell anergy and peripheral T–cell tolerance." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1409 (May 29, 2001): 625–37. http://dx.doi.org/10.1098/rstb.2001.0844.

Full text

Abstract:

The discovery that T–cell recognition of antigen can have distinct outcomes has advanced understanding of peripheral T–cell tolerance, and opened up new possibilities in immunotherapy. Anergy is one such outcome, and results from partial T–cell activation. This can arise either due to subtle alteration of the antigen, leading to a lower–affinity cognate interaction, or due to a lack of adequate co–stimulation. The signalling defects in anergic T cells are partially defined, and suggest that T–cell receptor (TCR) proximal, as well as downstream defects negatively regulate the anergic T cell's ability to be activated. Most importantly, the use of TCR–transgenic mice has provided compelling evidence that anergy is an in vivo phenomenon, and not merely an in vitro artefact. These findings raise the question as to whether anergic T cells have any biological function. Studies in rodents and in man suggest that anergic T cells acquire regulatory properties; the regulatory effects of anergic T cells require cell to cell contact, and appear to be mediated by inhibition of antigen–presenting cell immunogenicity. Close similarities exist between anergic T cells, and the recently defined CD4 + CD25 + population of spontaneously arising regulatory cells that serve to inhibit autoimmunity in mice. Taken together, these findings suggest that a spectrum of regulatory T cells exists. At one end of the spectrum are cells, such as anergic and CD4 + CD25 + T cells, which regulate via cell–to–cell contact. At the other end of the spectrum are cells which secrete antiinflammatory cytokines such as interleukin 10 and transforming growth factor–β. The challenge is to devise strategies that reliably induce T–cell anergy in vivo , as a means of inhibiting immunity to allo– and autoantigens.

APA, Harvard, Vancouver, ISO, and other styles

10

Yu, Hong, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo Vignali, Ying Zheng, Andriana Lebid, et al. "The neurotrophic factor Neuritin regulates T cell anergy and T regulatory cell function." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 56.03. http://dx.doi.org/10.4049/jimmunol.208.supp.56.03.

Full text

Abstract:

Abstract T cell activation and tolerance are tightly regulated to ensure effective elimination of foreign antigen while maintaining immune tolerance to self-antigens. Development of T cell anergy and regulatory T cell (Treg) mediated suppression both contribute to the establishment of immune tolerance. Here, we show that neuritin (Nrn1), a conserved GPI-anchored surface molecule important for the development, survival and function of neurons, is highly expressed in anergic and Treg cells. Nrn1 deficient CD4 cells are resistant to Treg cell mediated suppression, display defective anergy induction, and have reduced peripheral Treg generation. Nrn1 deficient Foxp3+ Treg cells exhibit reduced control of inflammatory colitis. Moreover, upon induction of experimental autoimmune encephalomyelitis (EAE), Nrn1 deficient mice develop non-remitting disease and have increased spinal cord inflammatory infiltrates. These in vivo findings underscore the importance of Nrn1 in immune tolerance. Recently, Nrn1 was identified as an accessory component of the ionotropic AMPA receptor (AMPAR) complex in neurons. AMPARs mediate glutamate dependent cation flux and regulate cell membrane potential. Cell membrane potential can impact nutrient uptake, calcium influx, cell size, proliferation and survival. In vitro analysis reveals that Nrn1 deficient Treg cells exhibit reduced proliferation and survival, associated with higher membrane potential, reduced nutrient sensitivity, reduced glycolysis and mTOR activation. AMPAR blockade can correct proliferation defect in Nrn1 deficient Treg cells. These findings reveal Nrn1 as an important regulator of immune tolerance functioning through the modulation of glutamate activated AMPAR.

APA, Harvard, Vancouver, ISO, and other styles

11

Dustin, Michael, Ahmed Saadawi, Viveka Mayya, Pablo Cespedes, Salvatore Valvo, Lina Chen, and Philippos Demetriou. "Dissection of T-cell tolerance induction by dendritic cell surface glycoproteins." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 143.1. http://dx.doi.org/10.4049/jimmunol.204.supp.143.1.

Full text

Abstract:

Abstract Tolerogenic dendritic cells (DC) induce T-cell clonal deletion, anergy, generation and activation of regulatory T cells. In vitro production of TolDC has been accomplished, however the full molecular circuitry is not known. We aim to decipher the chemical signals and physical characteristics leading to T-cell tolerance in an artificial system. We have performed surface proteomic analysis of human peripheral blood cDC2 subset without and with in vitro stimulation with polyIC in vitro. The surface proteomics is based on biotinylation of sialic acids and the signal strength was 55-fold higher in the resting compared to the activated condition, presumably due to decreased sialation of glycoproteins in the activated cDC2. We found that label free quantification (LFQ), corrected for differences in sialation, agreed well with quantitative surface expression by flow cytometry. We combined the two datasets and ranked the top 120 glycoproteins with extracellular domains (ECD) > 60 amino acids by LFQ with approximately one third invariant, one third up-regulated/induced and one one-third down-regulated/lost on activation. The 120 ECD were expressed in HEK293 cells with C-terminal 10His tags and purified by Ni2+ affinity chromatography. Supported lipids bilayers (SLB) representing the tolerogenic and activating DC are being designed with different combinations of the 120 ECDs. We will adjust sialation to match resting and activated states. The SLB compositions will be tested for immunological synapse formation (fluorescent self-pMHC/CD80, ICAM-1 and CD58 for the cSMAC, pSMAC and dSMAC) and tolerance/activation spectrum with identification of relevant molecular combinations by machine learning.

APA, Harvard, Vancouver, ISO, and other styles

12

Dutta, Avijit, Charles Drake, Jonathan Powell, Drew Pardoll, and Ching-Tai Huang. "Reduced T-bet induction in proliferation- interferon-γ decoupled CD4+ T cells as a mechanism for propagated T cell tolerance (IRC4P.491)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 60.18. http://dx.doi.org/10.4049/jimmunol.192.supp.60.18.

Full text

Abstract:

Abstract Infectious tolerance of immunity has been proposed as a mechanism of tolerance propagation. Limited effort of tolerance induction may be exploited for maintaining stable long-term tolerance. In our hemagglutinin (HA) antigen-specific transgenic mouse model system, adoptively transferred naïve HA-specific CD4+ T cells became tolerized in HA bearing mice and developed into regulatory T cells (Treg) with LAG-3 expression. These Treg suppressed the activation of secondly transferred naïve HA-specific CD4+ T cells. The suppressed HA-specific CD4+ T cells of second transfer were impaired for their IFN-γ capacity with reduced T-bet induction and STAT1 phosphorylation. However, they still substantially proliferated and acquired LAG-3 expression. They themselves became regulatory T cells as well. They further suppressed HA specific naïve CD4+ T cells both in vitro and in vivo. Compromised T-bet induction and IFN-γ capacity with T cell activation under Treg suppression ensure the transition into Treg without significant effector activity and ultimate propagated tolerance.

APA, Harvard, Vancouver, ISO, and other styles

13

Yi, Jaeu, Jisun Jung, Sung-Wook Hong, Jun Young Lee, Daehee Han, Kwang Soon Kim, Jonathan Sprent, and Charles D. Surh. "Unregulated antigen-presenting cell activation by T cells breaks self tolerance." Proceedings of the National Academy of Sciences 116, no. 3 (December 31, 2018): 1007–16. http://dx.doi.org/10.1073/pnas.1818624116.

Full text

Abstract:

T cells proliferate vigorously following acute depletion of CD4+ Foxp3+ T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1−/− hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies.

APA, Harvard, Vancouver, ISO, and other styles

14

Burtles, S. S., S. Trembleau, K. Drexler, and U. Hurtenbach. "Absence of T cell tolerance to pancreatic islet cells." Journal of Immunology 149, no. 6 (September 15, 1992): 2185–93. http://dx.doi.org/10.4049/jimmunol.149.6.2185.

Full text

Abstract:

Abstract To examine whether the lack of self-tolerance to beta cells is responsible for the development of type I diabetes in nonobese diabetic (NOD) mice, we attempted to induce T cell responses to cells from the islets of Langerhans. The data show that all NOD mice, irrespective of age, sex, and disease progression, possess islet cell-specific CD4+, MHC class II-restricted T cells. Both primary and secondary proliferative responses to islet cells were readily induced. The activation of T cells required presentation of islet cell Ag by APC in the responding lymph node cell population. Cells from other tissues, e.g., salivary gland, adrenal gland, and spleen, failed to activate autologous T lymphocytes. T cells specific for other Ag did not respond to islet cells, indicating that the proliferation is not the result of nonspecific stimulation by islet cell products. The presence of islet cell-reactive T cells is, however, not unique to NOD mice, because similar T cell reactivity was also demonstrated in non-diabetes-prone mouse strains. Hence, self-tolerance to islet cells appears to be absent. The results indicate a normal occurrence of islet cell-reactive T cells in both diabetes-prone as well as non-diabetes-prone mice. Thus, the lack of tolerance cannot be the initial cause of diabetes, but the activation of such autoreactive T cells may be important for the development of the disease.

APA, Harvard, Vancouver, ISO, and other styles

15

Klann, Jane E., Stephanie H. Kim, Kelly A. Remedios, Zhaoren He, Patrick J. Metz, Justine Lopez, Tiffani Tysl, et al. "Integrin Activation Controls Regulatory T Cell–Mediated Peripheral Tolerance." Journal of Immunology 200, no. 12 (April 27, 2018): 4012–23. http://dx.doi.org/10.4049/jimmunol.1800112.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

Blanden, R. V., P. D. Hodgkim, A. Hill, V. G. Sinickas, and A. Mullbacher. "Quantitative Considerations of T-Cell Activation and Self Tolerance." Immunological Reviews 98, no. 1 (August 1987): 75–93. http://dx.doi.org/10.1111/j.1600-065x.1987.tb00520.x.

Full text

APA, Harvard, Vancouver, ISO, and other styles

17

Zhang, Y., Y. Chung, C. Bishop, B. Daugherty, H. Chute, P. Holst, C. Kurahara, et al. "Regulation of T cell activation and tolerance by PDL2." Proceedings of the National Academy of Sciences 103, no. 31 (July 24, 2006): 11695–700. http://dx.doi.org/10.1073/pnas.0601347103.

Full text

APA, Harvard, Vancouver, ISO, and other styles

18

You, Qiang, Linling Cheng, and Cynthia Ju. "Role of Hepatic Kupffer Cells in Inducing T cell Tolerance (128.12)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S212. http://dx.doi.org/10.4049/jimmunol.178.supp.128.12.

Full text

Abstract:

Abstract The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KC could induce T cell tolerance by acting as ¡°poor¡± antigen presenting cells, as well as an active suppressor of T cell activation. The phenotypes of KC were characterized by flow cytometry. The abilities of KC to activate T cells and to suppress T cell activation induced by spleen dendritic cells (DC) were examined by in vitro proliferation assays using OTII cells. We found that, comparing with DC, KC expressed significantly lower levels of MHCII, B7.1, B7.2, and CD40. This is consistent with our observation that KC were not as potent as DC in eliciting OVA-specific T cell proliferation. More importantly, we found that KC could inhibit DC-induced OVA-specific T cell response. Further investigation of the mechanism involved in such suppression revealed that KC could induce apoptosis of the activated T cells. In summary, our data suggest that KC are ¡°poor¡± stimulators of T cells, and that they can cause tolerance through induction of T cell apoptosis. These findings indicate that KC play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance.

APA, Harvard, Vancouver, ISO, and other styles

19

Monaco, Sara, Beate Jahraus, Yvonne Samstag, and Hilmar Bading. "Nuclear calcium is required for human T cell activation." Journal of Cell Biology 215, no. 2 (October 17, 2016): 231–43. http://dx.doi.org/10.1083/jcb.201602001.

Full text

Abstract:

Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show that the “T cell calcium signal” is a composite signal harboring two distinct components that antagonistically control genomic programs underlying the immune response. Using human T cells from healthy individuals, we establish nuclear calcium as a key signal in human T cell adaptogenomics that drives T cell activation and is required for signaling to cyclic adenosine monophosphate response element–binding protein and the induction of CD25, CD69, interleukin-2, and γ-interferon. In the absence of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calcium–driven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy.

APA, Harvard, Vancouver, ISO, and other styles

20

Tsai, Kevin, Yu-Hsuan Huang, Xiaoxia Wang, and John J. Priatel. "Dual T cell receptor-expressing CD8 T cells potentiate autoreactivity." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 186.27. http://dx.doi.org/10.4049/jimmunol.196.supp.186.27.

Full text

Abstract:

Abstract Central tolerance serves to eliminate newly developing T cells that express strongly autoreactive T cell receptors. Although central tolerance is efficient in deleting high avidity autoreactive T cells, some lower avidity autoreactive T cells escape negative selection to cause autoimmune diseases. Although tight allelic exclusion limits thymocytes to expressing a single TCRbeta chain, rearrangement of the TCRalpha chain continues unabated until halted by positive selection, enabling thymocytes to express up to two TCRalpha chains and thus two TCRs. Moreover, it has been postulated that pathogenic low avidity autoreactive CD8 T cells may escape central tolerance through expression of a secondary benign TCR that mediates positive selection. To determine the role of dual TCR expressing CD8 T cells in autoreactivity and autoimmunity, we have compared CD8 T cell autoreactivity against the model autoantigen ovalbumin between T cells capable of expressing two TCRs (TCRalpha+/+) versus T cells capable of expressing a single TCR (TCRalpha+/−). TCRalpha+/− CD8 T cells exhibited reduced proliferative capacity upon OVA stimulation relative to TCRalpha+/+ CD8 T cells. In addition, a lower frequency of TCRalpha+/− CD8 T cell effectors produced IFN-gamma upon activation with OVA compared to TCRalpha+/+ CD8 T cell effectors. Taken together, we shown that dual TCR expression by CD8 T cells reduces the efficiency of T cell tolerance and may potentiate T cell autoreactivity. We are investigating whether dual TCR-expressing T cells are key to the pathogenesis of autoimmune diabetes in our mouse model system. Our results will provide valuable insight into the escape mechanisms exploited by pathogenic autoreactive CD8 T cells.

APA, Harvard, Vancouver, ISO, and other styles

21

Hsiao, Huey-Wen, and Ming-Zong Lai. "The role of deltex1 in regulating T cell tolerance (63.20)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 63.20. http://dx.doi.org/10.4049/jimmunol.186.supp.63.20.

Full text

Abstract:

Abstract Deltex1 (DTX1) is an E3 ubiquitin ligase and is suggested to be a mediator of Notch signaling. Our previous study found that DTX1 supressses T cell activation and promotes MEKK1 degradation. In this study, we found that T cell activation was partially suppressed by DTX1 with either inactive mutation of RING finger domain or deletion of WWE domain. In addition, we identified another suppressive mechanism of DTX1 by upregulation of Gadd45β, an inhibitor of JNK activation. DTX1 may promote the expression of Gadd45β in the absence of RF domain or WWE domain. Therefore, DTX1 inhibit T cell activation by either E3-dependent or E3-independent mechanisms. To further investigate the physiological function of DTX1 in lymphocyte development and activation, Dtx1-deficient mice were generated. T cell development in thymus and spleen was normal. B cell development in bone marrow was not affected but margine zone B cell population in spleen was reduced in Dtx1-deficient mice. T cell proliferation, cytokine production and MAPK activation were enhanced in Dtx1-deficient T cells. In addition, enhanced autoantibody production, elevated immune complex deposition in kidney and increased leukocyte infiltration in lung and liver were observed in aged Dtx1-deficient mice. These results suggest that DTX1 plays a role in T cell tolerance induction.

APA, Harvard, Vancouver, ISO, and other styles

22

Liu, Xikui, Maria Alexiou, Natalia Martin-Orozco, Yeonseok Chung, Roza Nurieva, Qiang Tian, Sijie Lu, George Kollias, Daniel Graf, and Chen Dong. "A critical role of BTLA in peripheral T cell tolerance induction (48.18)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 48.18. http://dx.doi.org/10.4049/jimmunol.182.supp.48.18.

Full text

Abstract:

Abstract T cell activation and tolerance are delicately regulated by costimulatory molecules. Although B and T lymphocyte attenuator (BTLA) has been shown as a negative regulator for T cells activation, its role in peripheral T cell tolerance induction in vivo has not been addressed. In this study, we generated a novel strain of BTLA-deficient mice, and employed three different models to characterize the function of BTLA in controlling T cell tolerance. In an oral tolerance model, BTLA-deficient mice were found resistant to the induction of T cell tolerance to an oral antigen. Moreover, compared with wild-type OT-II cells, BTLA-/- OT-II cells were less susceptible to tolerance induction by high-dose Ova peptide administered intravenously. Finally, BTLA-/- OT-I cells caused autoimmune diabetes in RIP-mOVA recipient mice. Our results thus demonstrate an important role of BTLA in the induction of peripheral tolerance of both CD4+ and CD8+ T cells in vivo.

APA, Harvard, Vancouver, ISO, and other styles

23

Nurieva, Roza, Shuling Zheng, Wei Jin, Shao-Cong Sun, Guillermina Lozano, and Chen Dong. "A critical role of GRAIL in T cell activation and tolerance (50.18)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 50.18. http://dx.doi.org/10.4049/jimmunol.184.supp.50.18.

Full text

Abstract:

Abstract T lymphocyte activation is tightly regulated to ensure effective elimination of invading pathogens as well as maintaining tolerance against self-tissues. Gene related to anergy in lymphocytes (GRAIL) is a type I transmembrane protein localized to endosomal compartment with homology to RING finger proteins whose expression was previously associated with induction of T cell tolerance in vitro. In order to understand the physiological function of GRAIL in immune regulation, we have generated and analyzed a Grail-deficient mouse model. We found that naïve T cells lacking GRAIL exhibited greatly enhanced proliferation and cytokine production after TcR activation and did not depend on CD28 and ICOS for their effector cytokine expression. We also determined that lack of GRAIL abrogated suppressive function of regulatory T cells. Both naïve and regulatory T cells from Grail-deficient mice were less efficient in down-regulation of their TcR/CD3 expression. In vivo, Grail-deficient mice were resistant to immune tolerance induction and when compared to the wild-type mice, exhibited greater susceptibility to autoimmune diseases. Our results thus indicate GRAIL as an essential regulator of T cell tolerance by regulating naïve T cell tolerance and regulatory T cell function.

APA, Harvard, Vancouver, ISO, and other styles

24

Wallet, Mark A., Pradip Sen, Rafael R. Flores, Yaming Wang, Zuoan Yi, Yingsu Huang, Clayton E. Mathews, et al. "MerTK is required for apoptotic cell–induced T cell tolerance." Journal of Experimental Medicine 205, no. 1 (January 14, 2008): 219–32. http://dx.doi.org/10.1084/jem.20062293.

Full text

Abstract:

Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.

APA, Harvard, Vancouver, ISO, and other styles

25

Hawiger, Daniel, Kayo Inaba, Yair Dorsett, Ming Guo, Karsten Mahnke, Miguel Rivera, Jeffrey V. Ravetch, Ralph M. Steinman, and Michel C. Nussenzweig. "Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo." Journal of Experimental Medicine 194, no. 6 (September 17, 2001): 769–80. http://dx.doi.org/10.1084/jem.194.6.769.

Full text

Abstract:

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

APA, Harvard, Vancouver, ISO, and other styles

26

Kline, Douglas E., Xiufen Chen, Dominick Fosco, and Justin Kline. "CD8α+ Dendritic Cells Induce Leukemia-Specific T cell Tolerance." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 211.15. http://dx.doi.org/10.4049/jimmunol.196.supp.211.15.

Full text

Abstract:

Abstract Antigen presenting cells (APCs) are critical for the acquisition of tumor-derived antigens and the orchestration of anti-tumor T cell responses. Batf3-dependent CD8α+ and CD103+ dendritic cells (DCs) have been implicated as the critical APCs that initiate and maintain spontaneous CD8+ T cell priming against solid tumors. In contrast, little is known about the APCs that regulate immunity against malignancies of hematopoietic origin. Using a murine model of acute myeloid leukemia (AML) that induces T cell tolerance, we demonstrate that leukemia-derived antigens are exclusively acquired and cross-presented by CD8α+ DCs. In the steady state, CD8α+ DCs rapidly induce leukemia-specific T cell tolerance, which can be prevented upon the activation of these DCs. Together, our data reveal that the same DC lineage can imprint disparate T cell fates in mice with solid verses hematopoietic malignancies. In the context of solid tumors, Batf3-dependent DCs stimulate productive effector responses; however, in AML-bearing mice, CD8α+ DCs actively promote T cell tolerance.

APA, Harvard, Vancouver, ISO, and other styles

27

Huang, Yafei, Ryan A. Heiser, Thiago O. Detanico, Andrew Getahun, Greg A. Kirchenbaum, Tamara L. Casper, M. Kemal Aydintug, et al. "γδ T cells affect IL-4 production and B-cell tolerance." Proceedings of the National Academy of Sciences 112, no. 1 (December 22, 2014): E39—E48. http://dx.doi.org/10.1073/pnas.1415107111.

Full text

Abstract:

γδ T cells can influence specific antibody responses. Here, we report that mice deficient in individual γδ T-cell subsets have altered levels of serum antibodies, including all major subclasses, sometimes regardless of the presence of αβ T cells. One strain with a partial γδ deficiency that increases IgE antibodies also displayed increases in IL-4–producing T cells (both residual γδ T cells and αβ T cells) and in systemic IL-4 levels. Its B cells expressed IL-4–regulated inhibitory receptors (CD5, CD22, and CD32) at diminished levels, whereas IL-4–inducible IL-4 receptor α and MHCII were increased. They also showed signs of activation and spontaneously formed germinal centers. These mice displayed IgE-dependent features found in hyper-IgE syndrome and developed antichromatin, antinuclear, and anticytoplasmic autoantibodies. In contrast, mice deficient in all γδ T cells had nearly unchanged Ig levels and did not develop autoantibodies. Removing IL-4 abrogated the increases in IgE, antichromatin antibodies, and autoantibodies in the partially γδ-deficient mice. Our data suggest that γδ T cells, controlled by their own cross-talk, affect IL-4 production, B-cell activation, and B-cell tolerance.

APA, Harvard, Vancouver, ISO, and other styles

28

Badami, Ester, Olivier N. F. Cexus, and Sonia Quaratino. "Activation-induced cell death of self-reactive regulatory T cells drives autoimmunity." Proceedings of the National Academy of Sciences 116, no. 52 (December 9, 2019): 26788–97. http://dx.doi.org/10.1073/pnas.1910281116.

Full text

Abstract:

Activation of self-reactive T cells is a major driver to autoimmunity and is suppressed by mechanisms of regulation. In a humanized model of autoimmune thyroiditis, we investigated the mechanism underlying break of tolerance. Here, we found that a human TCR specific for the self-antigen thyroid peroxidase (TPO) is positively selected in the thymus of RAG KO mice on both T effector (Teff) and T regulatory (Treg) CD4+Foxp3+cells. In vivo Teffare present in all immune organs, whereas the TPO-specific Tregare present in all lymphoid organs with the exception of the thyroid-draining lymph nodes. We suggest that the presence of TPO in the thyroid draining lymph nodes induces the activation of Teffand the depletion of Tregvia activation-induced cell death (AICD). Our findings provide insights on the failure of the mechanisms of immune tolerance, with potential implications in designing immunotherapeutic strategies.

APA, Harvard, Vancouver, ISO, and other styles

29

Klann, Jane Elizabeth, Stephanie H. Kim, Kelly A. Remedios, Patrick J. Metz, Adam K. Snider, Justine Lopez, Joseph M. Cantor, et al. "Integrin activation controls regulatory T cell identity and stability." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 125.3. http://dx.doi.org/10.4049/jimmunol.196.supp.125.3.

Full text

Abstract:

Abstract Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and β subunits that mediate cell-cell and cell-extracellular matrix interactions, have been shown to play an important role in facilitating cell contact-mediated suppression by Treg cells. Here we show that integrin activation plays an essential, previously unappreciated role in maintaining the stability of the Treg cell pool. Treg cell-specific loss of talin1, a β integrin-binding protein, or expression of talin1(L325R), a mutant that selectively abrogates integrin activation, resulted in dysregulation of Treg cell identity and lethal systemic autoimmunity. Moreover, the absence of sustained interactions between the integrin LFA-1 on Treg cells and its ligand ICAM-1 on dendritic cells reduced the expression of Foxp3 and caused Treg cells to adopt an effector CD4+ T cell-like phenotype. Taken together, these results reveal a critical role for tonic, integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell identity and stability.

APA, Harvard, Vancouver, ISO, and other styles

30

Yu, Miao, Gang Guo, Wei Xiao, and Yan Cui. "Fibroblastic reticular cells of the secondary lymphoid organ suppress T cell activation via COX2 mediated PGE2 secretion." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 55.31. http://dx.doi.org/10.4049/jimmunol.196.supp.55.31.

Full text

Abstract:

Abstract Accumulating evidence demonstrates that fibroblastic reticular cells (FRCs) in the T cell zone of the secondary lymphoid organs (SLO), characterized as CD45− gp38+CD31− cells, play an important role in maintaining T cell tolerance via presenting peripheral tissue–restricted antigens (PTAs) and/or interferon-induced nitric oxide during productive immunity. Here, using FRCs harvested from naïve mice, we revealed that FRCs also inhibit T cell activation via a soluble factor, independent of the aforementioned mechanisms. Specifically, FRCs suppressed CD3/CD28-ligation mediated or antigen induced antigen-specific T cell activation. This FRC-imposed suppression was demonstrated as (1) reduced Zap-70 phosphorylation and Calcium-flux within 30 minutes of TCR-ligation, (2) inhibited upregulation of surface CD69 and CD44 expression and downregulation of CD62L 6–14 hours post-activation, and (3) suppressed T cell effector cytokine production and proliferation. Further studies demonstrated that our observed inhibition of T cell activation by FRC is at least partially contributed by cyclooxygenase-2 (COX-2) mediated production of prostaglandin E2 (PGE2) because COX-2 inhibitor partially reversed FRC mediated inhibition. ELISA results confirmed high production level of PGE2 by FRC (~ 10 – 50ng/ml), at which level T cell activation is greatly suppressed. Taken together, our study illustrated another previously unrecognized mechanism of FRCs in maintaining T cell tolerance, which underscores the crucial role of FRCs in peripheral tolerance and immune regulation. The potential molecular mechanism by which the COX2-PGE2 pathway is activated in FRCs under physiological condition will be discussed.

APA, Harvard, Vancouver, ISO, and other styles

31

Kissick, Haydn, Jorge Finke, Laura Dunn, John Asara, Martin Sanda, and M. Simo Arredouani. "Metabolic profiling of T-cell differentiation and tolerance (115.5)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 115.5. http://dx.doi.org/10.4049/jimmunol.188.supp.115.5.

Full text

Abstract:

Abstract Metabolic pathways that drive T cell differentiation, activation and tolerance remain poorly understood. Here we used mass spectrometry to partially describe the metabolic profile of CD4 and CD8 T cells that underwent in vitro activation and differentiation in the presence or absence of prostate cancer conditioned media. T cell subsets were purified from mouse spleen or human PBMC, activated in vitro in the presence of various combinations of cytokines or prostate cancer cell line conditioned media. Metabolites were extracted using methanol, injected and analyzed using a 5500 QTRAP triple quadruple mass spectrometer coupled to a Prominence UFLC HPLC system via selected reaction monitoring (SRM) of a total of 255 endogenous water soluble metabolites for steady-state analyses of samples. Our data show that TCR/CD28-mediated activation imposes a distinct metabolic profile on mouse T cells. This profile is distinct for each cell lineage when activated cells are differentiated into either Th1, Th2, Th9, Th17 or regulatory T cell phenotypes. Likewise, metabolic profiles of activated CD4 and CD8 T cells from both mouse and human are significantly affected by the presence of prostate cancer cell line conditioned media, with major changes in the urea cycle, ammonia recycling, and protein and nucleotide biosynthesis . Together, our findings provide a basis for further development of drugs that could be used to manipulate T cells for a better outcome of prostate cancer vaccines.

APA, Harvard, Vancouver, ISO, and other styles

32

Bumpus, Tia, and Ann Marshak-Rothstein. "Autoreactive T cell activation is sufficient for breaking B cell tolerance in the setting of functional antigen-specific dominant tolerance (P4543)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 197.6. http://dx.doi.org/10.4049/jimmunol.190.supp.197.6.

Full text

Abstract:

Abstract Systemic lupus erythematosus is a multisystem autoimmune disease characterized by anti-nuclear autoantibody (ANA) production by activated autoreactive B cells and the persistence and activation of autoreactive T cells. Animal models of lupus provide evidence that T and B cells interact to drive autoimmunity. Whether a break in tolerance in the T cell or B cell compartment could lead to a break in tolerance in the other compartment is unclear. Several studies have addressed this issue using transgenic autoreactive B cells, but whether significant elaboration of autoreactive B cells in the normal repertoire can be driven by activated T cells has not been shown. To address this question, we developed a mouse model in which naïve or activated transgenic autoreactive CD4+ T cells are transferred into hosts expressing their cognate pseudo-autoantigen (autoAg) on B cells and other antigen presenting cells (APCs). Interestingly, autoAg-specific Th1 or Th2 cells, but not naïve cells, drive ANA production by endogenous autoreactive B cells. In bone marrow chimeras, autoAg expression by radioresistant APCs was crucial for sufficient suppression of B cell activation by activated T cells. Additonally, we found that radioresistant APCs most effectively activate autoAg-specific splenic Tregs. We have shown that T cell activation is an important checkpoint in the prevention of ANA production by autoreactive B cells and that antigen-specific Tregs most effectively control ANA production.

APA, Harvard, Vancouver, ISO, and other styles

33

Shah, Shivanee, and Liang Qiao. "Role of Epitope Valency in inducing Tolerance or Immunity (88.34)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S145. http://dx.doi.org/10.4049/jimmunol.178.supp.88.34.

Full text

Abstract:

Abstract Different antigens result in different immune responses. Soluble antigens, such as food, are tolerogenic; whereas microbes, which generally have repeating eptitopes, are immunogenic. Thus, we hypothesize that epitope valency of the antigen plays a role in deciding the immune outcome. B cells are antigen presenting cells that specifically recognize antigenic epitopes and become activated in the presence of multi-valent epitopes. Thus, we studied the effect of different epitope valencies on B cell activation and consequently T cell activation. Using monovalent and divalent fragments of the same antigen, we determined B cell activation markers by flow cytometry; and T cell activation by proliferation assays and cytokine analysis (ELISA). We found that like unstimulated B cells, univalent epitopes cannot activate B cells but can expand a population of CD4+CD25+Foxp3+T cells (Tregs); whereas divalent epitopes activate B cells and consequently help T cell activation, but do not induce T regs. Interestingly, the mechanism of expansion of this Treg population is via TGFβ3 and not via known cytokines TGFβ1 or IL-10. This implies not only that structure of the antigen plays a critical role in setting off a competitive immune response, but also that resting B cells can maintain a population of regulatory T cells that can prevent the activation of self-reactive T cells and thus prevent autoimmunity.

APA, Harvard, Vancouver, ISO, and other styles

34

Fu, Guoping, Yuhong Chen, Mei Yu, Andy Podd, James Schuman, Yinghong He, Lie Di, et al. "Phospholipase Cγ1 is essential for T cell development, activation, and tolerance." Journal of Experimental Medicine 207, no. 2 (February 1, 2010): 309–18. http://dx.doi.org/10.1084/jem.20090880.

Full text

Abstract:

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance.

APA, Harvard, Vancouver, ISO, and other styles

35

Chaudhuri, Shuvam Mohan, Yana Zhang, Samuel E. Weinberg, and Deyu Fang. "Mediator complex maintains peripheral T cell tolerance through enforcement of the quiescence module." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 166.13. http://dx.doi.org/10.4049/jimmunol.208.supp.166.13.

Full text

Abstract:

Abstract T cell tolerance has traditionally been thought to be maintained at stages after T cell receptor mediated activation either through anergy, exhaustion, contraction or T Regulatory cell mediated dominant suppression. Prior to these mechanisms, however, T cell quiescence is the main factor maintaining T cell tolerance. We have identified Mediator Complex Subunit 1 (Med1), as a novel factor responsible for enforcing T cell quiescence. Mice with T cell specific deletion of Med1 display increased levels of T cell activation despite having a normally functional T Regulatory cell compartment. Med1-deficient T cells were more responsive to T cell receptor mediated activation. Bone marrow chimeras revealed Med1 controls T cell quiescence in a cell intrinsic manner. Bulk and single cell transcriptome sequencing revealed Med1’s transcriptional control over key quiescence factors. By analyzing previously published chromatin immunoprecipitation sequencing we found Med1 controlled a transcription factor network rather than direct quiescence molecules. Med1 is a novel factor responsible for actively enforcing the transcriptional network maintaining T cell quiescence. Supported by T32DK007169 R01CA257520 R01CA232347

APA, Harvard, Vancouver, ISO, and other styles

36

Ke, Y., K. Pearce, J. P. Lake, H. K. Ziegler, and J. A. Kapp. "Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance." Journal of Immunology 158, no. 8 (April 15, 1997): 3610–18. http://dx.doi.org/10.4049/jimmunol.158.8.3610.

Full text

Abstract:

Abstract Oral administration of Ag, over a period of several days, induces a state of tolerance that is associated with activation of CD8+ T cells that can transfer unresponsiveness to naive syngeneic hosts. We previously demonstrated that these T cells are not CTL precursors and that they inhibit responses by CD8+ CTL, as well as Ab and CD4+ T cell responses. Activation of noncytolytic, CD8+ suppressor T cells by oral Ag is a process that is not understood. In these studies, we asked whether depletion of the gamma delta T cells altered induction of oral tolerance. Injection of the anti-delta-chain Ab (GL3) down-modulated the expression of gamma delta TCR and inhibited the induction of oral tolerance to OVA, as measured by Ab, CD4+, and CD8+ T cell responses. GL3 did not activate IL-2 secretion that could be detected in the serum, nor did it induce IL-2R expression by intraepithelial lymphocytes, suggesting that GL3 inhibited the function of gamma delta T cells rather than activating them. This interpretation is supported by our observation that oral administration of Ag did not induce tolerance in TCR-delta knockout mice. These data suggest that gamma delta T cells play a critical, active role in tolerance induced by orally administered Ag.

APA, Harvard, Vancouver, ISO, and other styles

37

Sun, Jiaren, Bernadette Dirden-Kramer, Komei Ito, Peter B. Ernst, and Nancy Van Houten. "Antigen-Specific T Cell Activation and Proliferation During Oral Tolerance Induction." Journal of Immunology 162, no. 10 (May 15, 1999): 5868–75. http://dx.doi.org/10.4049/jimmunol.162.10.5868.

Full text

Abstract:

Abstract One of several routes of achieving immunologic tolerance is through functional inactivation of Ag-specific T cells. Oral administration of Ag can allow survival of the Ag-specific T cells that are functionally anergic. The aim of this study was to investigate whether functional inactivation of Ag-specific T cells is directed through an activation process and to further define the differentiative pathways and functional characteristics of anergic T cells. Mice were transplanted with OVA-specific TCR-transgenic T cells and either fed OVA or immunized s.c. with the OVA peptide 323–339 in CFA. OVA-specific T cells from OVA-fed mice were unresponsive to restimulation in vitro within 48–72 h after treatment. In vivo, however, T cell proliferation was detected by 5,6-carboxy-succinimidyl-fluoresceine-ester intensity changes in OVA-specific T cells. The mesenteric lymph nodes (LNs) from OVA-fed mice more frequently contained OVA-specific dividing cells in vivo than those in the peripheral LNs, and the reciprocal was observed following s.c. immunization of the OVA peptide in CFA. The induction of anergy in OVA-fed mice was accompanied by rapid up-regulation of CD69 and CTLA-4, later down-regulation of CD45RB on OVA-specific T cells, and a marked decrease in T cell secretion of IL-2, IL-10, and IFN-γ after OVA restimulation in vitro. Results from this study indicate that the inductive phase of oral tolerance is preceded by Ag-specific T cell activation in vivo, proliferation in the regional draining LNs, and differentiation into a memory-like state. These results indicate that Ag-directed differentiation occurs as a part of T cell tolerance through anergy.

APA, Harvard, Vancouver, ISO, and other styles

38

Garza, Kristine M., Steven M. Chan, Rakesh Suri, Linh T. Nguyen, Bernhard Odermatt, Stephen P. Schoenberger, and Pamela S. Ohashi. "Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity." Journal of Experimental Medicine 191, no. 11 (June 6, 1999): 2021–28. http://dx.doi.org/10.1084/jem.191.11.2021.

Full text

Abstract:

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

APA, Harvard, Vancouver, ISO, and other styles

39

Zhang, Ejuan, Hu Yan, Qian Li, Ulf Dittmer, Huimin Yan, and Mengji Lu. "Activation of the TLR signaling pathway in CD8+ T cells counteracts liver endothelial cell-induced T cell tolerance." Cellular & Molecular Immunology 16, no. 9 (June 26, 2019): 774–76. http://dx.doi.org/10.1038/s41423-019-0255-8.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Groom, Joanna R., Carrie A. Fletcher, Stacey N. Walters, Shane T. Grey, Sally V. Watt, Mathew J. Sweet, Mark J. Smyth, Charles R. Mackay, and Fabienne Mackay. "BAFF and MyD88 signals promote a lupuslike disease independent of T cells." Journal of Experimental Medicine 204, no. 8 (July 30, 2007): 1959–71. http://dx.doi.org/10.1084/jem.20062567.

Full text

Abstract:

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell–intrinsic signals through the Toll-like receptor (TLR)–associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell–independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.

APA, Harvard, Vancouver, ISO, and other styles

41

Kalergis, Alexis M., and Jeffrey V. Ravetch. "Inducing Tumor Immunity through the Selective Engagement of Activating Fcγ Receptors on Dendritic Cells." Journal of Experimental Medicine 195, no. 12 (June 17, 2002): 1653–59. http://dx.doi.org/10.1084/jem.20020338.

Full text

Abstract:

Induction of tumor-specific immunity requires that dendritic cells (DCs) efficiently capture and present tumor antigens to result in the expansion and activation of tumor-specific cytotoxic T cells. The transition from antigen capture to T cell stimulation requires a maturation signal; in its absence tolerance, rather than immunity may develop. While immune complexes (ICs) are able to enhance antigen capture, they can be poor at inducing DC maturation, naive T cell activation and protective immunity. We now demonstrate that interfering with the inhibitory signal delivered by FcγRIIB on DCs converts ICs to potent maturation agents and results in T cell activation. Applying this approach to immunization with DCs pulsed ex-vivo with ICs, we have generated antigen-specific CD8+ T cells in vivo and achieved efficient protective immunity in a murine melanoma model. These data imply that ICs may normally function to maintain tolerance through the binding to inhibitory FcγRs on DCs, but they can be converted to potent immunogenic stimuli by selective engagement of activating FcγRs. This mechanism suggests a novel approach to the development of tumor vaccines.

APA, Harvard, Vancouver, ISO, and other styles

42

Yin, Xiangyun, Shuting Chen, and Stephanie C. Eisenbarth. "Dendritic Cell Regulation of T Helper Cells." Annual Review of Immunology 39, no. 1 (April 26, 2021): 759–90. http://dx.doi.org/10.1146/annurev-immunol-101819-025146.

Full text

Abstract:

As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.

APA, Harvard, Vancouver, ISO, and other styles

43

Takahashi, Takeshi, Tomoyuki Tagami, Sayuri Yamazaki, Toshimitsu Uede, Jun Shimizu, Noriko Sakaguchi, Tak W. Mak, and Shimon Sakaguchi. "Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4." Journal of Experimental Medicine 192, no. 2 (July 17, 2000): 303–10. http://dx.doi.org/10.1084/jem.192.2.303.

Full text

Abstract:

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.

APA, Harvard, Vancouver, ISO, and other styles

44

Rausch, Matthew, Todd Metzger, Mark Anderson, and Karen Hastings. "GILT regulates CD4+ T cell tolerance (100.28)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 100.28. http://dx.doi.org/10.4049/jimmunol.186.supp.100.28.

Full text

Abstract:

Abstract Regulating the balance between T cell activation and tolerance is essential for stimulating an anti-tumor immune response and in controlling autoimmunity. We have shown that gamma-interferon-inducible lysosomal thiol reductase (GILT) is required for efficient MHC class II-restricted processing of an epitope from the melanoma antigen tyrosinase-related protein 1 (TRP1). Using CD4+ TRP1-specific T cell receptor transgenic mice, here we demonstrate a novel function for GILT in the regulation of TRP1-specific T cell tolerance. TRP1-specific T cells are centrally deleted in mice expressing both GILT and TRP1 on the RAG-/- background. In contrast, CD4+ T cells develop in the absence of either GILT or TRP1. GILT’s role in central tolerance is supported by GILT and TRP1 expression in thymic stromal cells. Although TRP1-specific CD4+ T cells escape thymic deletion in the absence of GILT, they are tolerant to TRP1 and do not induce vitiligo. TRP1-specific T cells from GILT-deficient mice initially divide in response to antigen, but fail to produce substantial levels of IFN-γ and IL-2. Tolerance is partially mediated by CD25+Foxp3+ regulatory T (Treg) cells. There is an increased percentage of TRP1-specific Treg cells in GILT-deficient compared to TRP1-deficient mice, and Treg cell depletion allows GILT-deficient TRP1-specific CD4+ T cells to induce vitiligo. These studies highlight a critical role for GILT in shaping the CD4+ T cell repertoire.

APA, Harvard, Vancouver, ISO, and other styles

45

This, Sébastien, Stefanie F. Valbon, Marie-Ève Lebel, and Heather J. Melichar. "Strength and Numbers: The Role of Affinity and Avidity in the ‘Quality’ of T Cell Tolerance." Cells 10, no. 6 (June 17, 2021): 1530. http://dx.doi.org/10.3390/cells10061530.

Full text

Abstract:

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the ‘function’ and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the ‘quality’ of anergic and regulatory T cell populations.

APA, Harvard, Vancouver, ISO, and other styles

46

Damo, Martina, and Nikhil S. Joshi. "The NINJA mouse: a novel model to study tissue-specific peripheral T cell tolerance." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 47.6. http://dx.doi.org/10.4049/jimmunol.200.supp.47.6.

Full text

Abstract:

Abstract T cell inhibitory pathways induce peripheral tolerance and have evolved to avoid pathogenic autoimmunity. Generally, peripheral tolerance either prevents T cell activation or inhibits T cells during chronic responses, but it is not clear whether these functions are orchestrated by the same mechanisms. Moreover, it is not known if these mechanisms have a tissue-specific usage. Persistent viral infections and cancer leverage the T cell inhibitory pathways involved in peripheral tolerance, thus providing translational relevance to the role of these pathways in disease. However, many of the mechanisms of peripheral tolerance remain understudied, in part because few animal models can distinguish these mechanisms from those driving central tolerance. We have generated a novel mouse model (iNversion INduced Joined neoAntigen, NINJA) that bypasses central and peripheral tolerance by using genetic recombination to create a neoantigen-coding gene for de novo neoantigen expression in any tissue of choice. NINJA expresses LCMV-derived GP33–41 and GP61–80 after induction, enabling investigation of tolerance using well established immunologic tools. Prior to recombination, NINJA mice respond robustly to LCMV-Arm infection, indicating absence of tolerance. However, after recombination, LCMV GP-specific responses are significantly impaired, although mice retain the capacity of developing immunity against unrelated LCMV epitopes. PD-1 is upregulated by tolerized endogenous GP33–41-specific CD8+ T cells after hepatocyte-specific NINJA activation, thus suggesting its involvement in hepatic peripheral tolerance. We therefore propose NINJA as a model to investigate tissue-specific mechanisms of peripheral T cell tolerance.

APA, Harvard, Vancouver, ISO, and other styles

47

Harlé, Guillaume, Camille Kowalski, Laure Garnier, and Stéphanie Hugues. "Lymph Node Stromal Cells: Mapmakers of T Cell Immunity." International Journal of Molecular Sciences 21, no. 20 (October 21, 2020): 7785. http://dx.doi.org/10.3390/ijms21207785.

Full text

Abstract:

Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.

APA, Harvard, Vancouver, ISO, and other styles

48

Katzman, S. D., W. E. O'Gorman, A. V. Villarino, E. Gallo, R. S. Friedman, M. F. Krummel, G. P. Nolan, and A. K. Abbas. "Duration of antigen receptor signaling determines T-cell tolerance or activation." Proceedings of the National Academy of Sciences 107, no. 42 (October 4, 2010): 18085–90. http://dx.doi.org/10.1073/pnas.1010560107.

Full text

APA, Harvard, Vancouver, ISO, and other styles

49

Fu, Guoping, Yuhong Chen, Mei Yu, Andy Podd, James Schuman, Yinghong He, Lie Di, et al. "Phospholipase Cg1 is essential for T cell development, activation, and tolerance." Journal of Cell Biology 188, no. 3 (February 8, 2010): i4. http://dx.doi.org/10.1083/jcb1883oia4.

Full text

APA, Harvard, Vancouver, ISO, and other styles

50

Vidard, L., L. J. Colarusso, and B. Benacerraf. "Specific T-cell tolerance may reflect selective activation of lymphokine synthesis." Proceedings of the National Academy of Sciences 92, no. 6 (March 14, 1995): 2259–62. http://dx.doi.org/10.1073/pnas.92.6.2259.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'T cell activation/tolerance'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles