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Journal articles on the topic 'T cell diversity'

Author: Grafiati

Published: 5 October 2024

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1

Newrzela, S., N. Al-Ghaili, T. Heinrich, M. Petkova, S. Hartmann, B. Rengstl, A. Kumar, et al. "T-cell receptor diversity prevents T-cell lymphoma development." Leukemia 26, no. 12 (May 30, 2012): 2499–507. http://dx.doi.org/10.1038/leu.2012.142.

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2

Stromberg, Sean P., and Jean M. Carlson. "Diversity of T-cell responses." Physical Biology 10, no. 2 (March 15, 2013): 025002. http://dx.doi.org/10.1088/1478-3975/10/2/025002.

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3

GORONZY, J., W. LEE, and C. WEYAND. "Aging and T-cell diversity☆." Experimental Gerontology 42, no. 5 (May 2007): 400–406. http://dx.doi.org/10.1016/j.exger.2006.11.016.

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4

Nelson, J. "STKE: Celebrating T Cell Diversity." Science 295, no. 5557 (February 8, 2002): 933b—933. http://dx.doi.org/10.1126/science.295.5557.933b.

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5

Robins, Harlan S., Paulo V. Campregher, Santosh K. Srivastava, Abigail Wacher, Cameron J. Turtle, Orsalem Kahsai, Stanley R. Riddell, Edus H. Warren, and Christopher S. Carlson. "Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells." Blood 114, no. 19 (November 5, 2009): 4099–107. http://dx.doi.org/10.1182/blood-2009-04-217604.

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Abstract The adaptive immune system uses several strategies to generate a repertoire of T- and B-cell antigen receptors with sufficient diversity to recognize the universe of potential pathogens. In αβ T cells, which primarily recognize peptide antigens presented by major histocompatibility complex molecules, most of this receptor diversity is contained within the third complementarity-determining region (CDR3) of the T-cell receptor (TCR) α and β chains. Although it has been estimated that the adaptive immune system can generate up to 1016 distinct αβ pairs, direct assessment of TCR CDR3 diversity has not proved amenable to standard capillary electrophoresis-based DNA sequencing. We developed a novel experimental and computational approach to measure TCR CDR3 diversity based on single-molecule DNA sequencing, and used this approach to determine the CDR3 sequence in millions of rearranged TCRβ genes from T cells of 2 adults. We find that total TCRβ receptor diversity is at least 4-fold higher than previous estimates, and the diversity in the subset of CD45RO+ antigen-experienced αβ T cells is at least 10-fold higher than previous estimates. These methods should prove valuable for assessment of αβ T-cell repertoire diversity after hematopoietic cell transplantation, in states of congenital or acquired immunodeficiency, and during normal aging.

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6

Sato, Kayoko. "Helper T Cell Diversity and Plasticity." Circulation Journal 78, no. 12 (2014): 2843–44. http://dx.doi.org/10.1253/circj.cj-14-1164.

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7

Born, Willi K., M. Kemal Aydintug, and Rebecca L. O'Brien. "Diversity of γδ T-cell antigens." Cellular & Molecular Immunology 10, no. 1 (October 22, 2012): 13–20. http://dx.doi.org/10.1038/cmi.2012.45.

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8

Parish, Ian A., and Susan M. Kaech. "Diversity in CD8+ T cell differentiation." Current Opinion in Immunology 21, no. 3 (June 2009): 291–97. http://dx.doi.org/10.1016/j.coi.2009.05.008.

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9

Nakayamada, Shingo, Hayato Takahashi, Yuka Kanno, and John J. O'Shea. "Helper T cell diversity and plasticity." Current Opinion in Immunology 24, no. 3 (June 2012): 297–302. http://dx.doi.org/10.1016/j.coi.2012.01.014.

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10

Kemir, C. "Diversity of Human T Cell Receptors." Science 288, no. 5469 (May 19, 2000): 1135a—1135. http://dx.doi.org/10.1126/science.288.5469.1135a.

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11

Leavy, Olive. "Unequal inheritance initiates T-cell diversity." Nature Reviews Immunology 7, no. 4 (April 2007): 247. http://dx.doi.org/10.1038/nri2064.

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12

Eugster, Anne, Annett Lindner, Anne-Kristin Heninger, Carmen Wilhelm, Sevina Dietz, Mara Catani, Anette-G. Ziegler, and Ezio Bonifacio. "Measuring T cell receptor and T cell gene expression diversity in antigen-responsive human CD4+ T cells." Journal of Immunological Methods 400-401 (December 2013): 13–22. http://dx.doi.org/10.1016/j.jim.2013.11.003.

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13

Elbe, Adelheid, Oliver Kilgus, Thomas Hünig, and Georg Stingl. "T-Cell Receptor Diversity in Dendritic Epidermal T Cells in the Rat." Journal of Investigative Dermatology 102, no. 1 (January 1994): 74–79. http://dx.doi.org/10.1111/1523-1747.ep12371735.

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14

Pacholczyk, Rafal, Hanna Ignatowicz, Piotr Kraj, and Leszek Ignatowicz. "Origin and T Cell Receptor Diversity of Foxp3+CD4+CD25+ T Cells." Immunity 25, no. 2 (August 2006): 249–59. http://dx.doi.org/10.1016/j.immuni.2006.05.016.

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15

Vats, Deepak, Geeta Rani, Alisha Arora, Vidushi Sharma, Isha Rathore, Shaikh Abdul Mubeen, and Archana Singh. "Tuberculosis and T cells: Impact of T cell diversity in tuberculosis infection." Tuberculosis 149 (December 2024): 102567. http://dx.doi.org/10.1016/j.tube.2024.102567.

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16

Davis, M. M. "T Cell Receptor Gene Diversity and Selection." Annual Review of Biochemistry 59, no. 1 (June 1990): 475–96. http://dx.doi.org/10.1146/annurev.bi.59.070190.002355.

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17

Koning, F., A. M. Kruisbeek, W. L. Maloy, S. Marusic-Galesic, D. M. Pardoll, E. M. Shevach, G. Stingl, R. Valas, W. M. Yokoyama, and J. E. Coligan. "T cell receptor gamma/delta chain diversity." Journal of Experimental Medicine 167, no. 2 (February 1, 1988): 676–81. http://dx.doi.org/10.1084/jem.167.2.676.

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The TCR-gamma and -delta chains of six murine hybridomas were compared by one-dimensional SDS-PAGE and two-dimensional NEPHGE/SDS-PAGE analysis. This allowed the identification of three distinct gamma chains (gamma a, gamma b, and gamma c) and three distinct delta chains (delta a, delta b, and delta c). Four gamma/delta chain combinations (gamma a delta a, gamma b delta b, gamma b delta c, and gamma c delta a) were observed. These results indicate that multiple forms of the delta chain are expressed and suggest that the delta chains are encoded for by an Ig-like rearranging gene. This delta chain polymorphism significantly enhances the potential diversity of TCR-gamma/delta, which may be of importance for a better understanding of the putative ligand(s) recognized by this receptor.

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18

Venet, Fabienne, Orchidée Filipe-Santos, Alain Lepape, Christophe Malcus, Françoise Poitevin-Later, Audrey Grives, Nadia Plantier, Nicolas Pasqual, and Guillaume Monneret. "Decreased T-Cell Repertoire Diversity in Sepsis." Critical Care Medicine 41, no. 1 (January 2013): 111–19. http://dx.doi.org/10.1097/ccm.0b013e3182657948.

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19

Turner, Stephen J., Nicole L. La Gruta, Katherine Kedzierska, Paul G. Thomas, and Peter C. Doherty. "Functional implications of T cell receptor diversity." Current Opinion in Immunology 21, no. 3 (June 2009): 286–90. http://dx.doi.org/10.1016/j.coi.2009.05.004.

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20

Haining, W. Nicholas. "The Numerology of T Cell Functional Diversity." Immunity 36, no. 1 (January 2012): 10–12. http://dx.doi.org/10.1016/j.immuni.2012.01.006.

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21

Liston, Adrian, and Daniel H. D. Gray. "Homeostatic control of regulatory T cell diversity." Nature Reviews Immunology 14, no. 3 (January 31, 2014): 154–65. http://dx.doi.org/10.1038/nri3605.

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22

Jameson, Stephen C., and David Masopust. "Understanding Subset Diversity in T Cell Memory." Immunity 48, no. 2 (February 2018): 214–26. http://dx.doi.org/10.1016/j.immuni.2018.02.010.

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23

Cannons, Jennifer L., Kristina T. Lu, and Pamela L. Schwartzberg. "T follicular helper cell diversity and plasticity." Trends in Immunology 34, no. 5 (May 2013): 200–207. http://dx.doi.org/10.1016/j.it.2013.01.001.

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24

Tognarelli, Eduardo I., Cristián Gutiérrez-Vera, Pablo A. Palacios, Ignacio A. Pasten-Ferrada, Fernanda Aguirre-Muñoz, Daniel A. Cornejo, Pablo A. González, and Leandro J. Carreño. "Natural Killer T Cell Diversity and Immunotherapy." Cancers 15, no. 24 (December 7, 2023): 5737. http://dx.doi.org/10.3390/cancers15245737.

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Invariant natural killer T cells (iNKTs), a type of unconventional T cells, share features with NK cells and have an invariant T cell receptor (TCR), which recognizes lipid antigens loaded on CD1d molecules, a major histocompatibility complex class I (MHC-I)-like protein. This interaction produces the secretion of a wide array of cytokines by these cells, including interferon gamma (IFN-γ) and interleukin 4 (IL-4), allowing iNKTs to link innate with adaptive responses. Interestingly, molecules that bind CD1d have been identified that enable the modulation of these cells, highlighting their potential pro-inflammatory and immunosuppressive capacities, as required in different clinical settings. In this review, we summarize key features of iNKTs and current understandings of modulatory α-galactosylceramide (α-GalCer) variants, a model iNKT cell activator that can shift the outcome of adaptive immune responses. Furthermore, we discuss advances in the development of strategies that modulate these cells to target pathologies that are considerable healthcare burdens. Finally, we recapitulate findings supporting a role for iNKTs in infectious diseases and tumor immunotherapy.

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25

Kedzierska, Katherine, Nicole L. La Gruta, John Stambas, Stephen J. Turner, and Peter C. Doherty. "Tracking phenotypically and functionally distinct T cell subsets via T cell repertoire diversity." Molecular Immunology 45, no. 3 (February 2008): 607–18. http://dx.doi.org/10.1016/j.molimm.2006.05.017.

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26

Chandra, Shilpi, Gregory Seumois, Ciro Ramirez, Gooyoung Seo, Pandurangan Vijayanand, and Mitchell Kronenberg. "Single cell sequencing reveals mouse MAIT cell diversity." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 65.1. http://dx.doi.org/10.4049/jimmunol.202.supp.65.1.

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Abstract Mucosal-associated invariant T (MAIT) cells are a novel subpopulation of innate-like T lymphocytes that recognize vitamin B metabolites and express an invariant T cell receptor (TCR) α chain. MAIT cells are less abundant in mouse blood (~0.1% of T cells) as compared to human blood (~5%). MAIT cells play an important role in various infectious non-infectious diseases. Given their small number in mouse, these cells have been not been fully characterized. To unravel MAIT cell heterogeneity in thymus and peripheral tissues, we have performed single-cell sequencing of MAIT cells from various organs using 10× single-cell genomics, where we sequenced more than 7,000 cells and identified 10 clusters of MAIT cells by unbiased clustering. Cells from different organs mostly are represented in the different clusters, except one cluster was lung MAIT cell specific and another cluster consisted of cells exclusively from thymus. The lung specific cluster also reveals a tissue residency gene signature. We compared the gene expression profile of MAIT cells with iNKT cells, another T lymphocyte population that recognizes non-peptide antigens with invariant α chains. Our data reveal that most mouse MAIT cells have a Th17/NKT17–like gene signature, although there are some with Th1/NKT1 like transcriptomes, particularly in liver and spleen. A Th2/NKT2 gene expression profile was not observed. The thymus specific cluster showed a gene expression profile similar to the most immature or progenitor iNKT cells (NKT0), consistent with other data suggesting a unique thymus differentiation pathway. Therefore, our study reveals that although MAIT cells are predominantly Th17 and Th1 cells, there is an unexpected degree of heterogeneity. Supported by R01 AI71922

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27

Tjoa, B., and D. M. Kranz. "Diversity of T cell receptor-alpha chain transcripts from hyperimmune alloreactive T cells." Journal of Immunology 149, no. 1 (July 1, 1992): 253–59. http://dx.doi.org/10.4049/jimmunol.149.1.253.

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Abstract Alloreactive T cells represent a relatively large fraction of the T cell population compared with the fraction of T cells that are specific for other foreign Ag. Recent findings indicate that most alloreactive T cells recognize endogenous peptides in association with a non-self MHC product. In light of these observations, it is perhaps not surprising that previous studies of the size of the TCR-alpha beta repertoire among alloreactive cells showed that they express many different V alpha and V beta genes. To further access the extent of diversity among alloreactive cells, we examined V alpha J alpha combinatorial diversity in polyclonal populations of a BALB/c anti-BALB.B mixed lymphocyte response. A long term culture from naive mice contained a diverse repertoire of V alpha J alpha combinations that was similar to the diversity present among unstimulated splenic T cells. In contrast, long term cultures from hyperimmunized animals contained "dominant" clones of T cells that expressed a restricted repertoire of V alpha J alpha combinations. Examination of the nucleotide sequences of these alpha-chains suggested that there was selective expansion of T cells with identical alpha-chains. In addition, T cells that express the same V alpha J alpha combination but different junctions were also identified. Consistent with previous results, the isolates from hyperimmune animals did not contain somatic mutations in the CDR3 region of the alpha-chains. Nevertheless, the results suggest that T cells may be subject to in vivo selection and clonal expansion analogous to the process of affinity maturation of Ig.

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28

Breit, T. M., I. L. M. Wolvers-Tettero, and J. J. M. van Dongen. "5.2 Receptor diversity of human T-cell receptor ?? expressing cells." Progress in Histochemistry and Cytochemistry 26, no. 1-4 (January 1992): 182–93. http://dx.doi.org/10.1016/s0079-6336(11)80094-x.

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29

Takeshita, Masaru, Katsuya Suzuki, Yoshiaki Kassai, Maiko Takiguchi, Yusuke Nakayama, Yuki Otomo, Rimpei Morita, Takahiro Miyazaki, Akihiko Yoshimura, and Tsutomu Takeuchi. "Polarization diversity of human CD4+ stem cell memory T cells." Clinical Immunology 159, no. 1 (July 2015): 107–17. http://dx.doi.org/10.1016/j.clim.2015.04.010.

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30

Campbell, Adana-Christine, Babak J. Mehrara, and Stav Brown. "T Cell Repertoire Diversity in Lymphedema: Investigating the Antigens Driving the T Cell Response." Plastic and Reconstructive Surgery - Global Open 10, no. 10S (October 2022): 107. http://dx.doi.org/10.1097/01.gox.0000898880.19929.aa.

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31

Knobloch, C., S. F. Goldmann, and W. Friedrich. "Limited T cell receptor diversity of transplacentally acquired maternal T cells in severe combined immunodeficiency." Journal of Immunology 146, no. 12 (June 15, 1991): 4157–64. http://dx.doi.org/10.4049/jimmunol.146.12.4157.

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Abstract Circulating maternal T lymphocytes were noted in the peripheral blood of six patients with severe combined immunodeficiency. Phenotypical analyses revealed the presence of both CD4 and CD8 subsets in some but not all cases. The maternal T cells could be stimulated by anti-TCR/CD3 mAb +/- rIL-2, but were virtually silent in the MLR and against the recall Ag purified protein derivative of tuberculin and tetanus toxoid, even in immunized patients engrafted with T cells from a responding mother. Using a panel of mAb against TCR V region gene encoded epitopes including V beta 5, V beta 6, V beta 8, V beta 12, and V alpha 2, we show that maternal T cells displayed a profoundly reduced TCR diversity, characterized by a lack of one or even several TCR V subsets in all six cases and a dramatic (5- to 25-fold) expansion of other TCR V subsets in three cases. In one patient analyzed, limited TCR diversity was also seen in T cells cultured from bone marrow and skin; restimulation experiments of these cells against cells expressing host MHC Ag were unsuccessful, as were attempts to exclusively allocate anti-host proliferative responses of maternal control T cells to the TCR V subsets that had undergone expansion in vivo. We conclude that a severely reduced TCR diversity is a common feature of maternal T cells engrafted in severe combined immunodeficiency patients. These novel findings provide a structural basis to understand the failure of these cells to protect the host from infections and may also help to understand their relative inefficiency to induce lethal, multi-organ, graft vs host disease. Moreover, as an experiment of nature, the reported phenomenon clearly illustrates the functional consequences in vivo of an insufficient TCR diversity.

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32

Horning, SJ, LM Weiss, GS Crabtree, and RA Warnke. "Clinical and phenotypic diversity of T cell lymphomas." Blood 67, no. 6 (June 1, 1986): 1578–82. http://dx.doi.org/10.1182/blood.v67.6.1578.1578.

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Abstract Forty-one cases of T cell lymphoma were identified on the basis of morphology and the expression of two or more T cell antigens with an absence of B cell markers. Mycosis fungoides and lymphoblastic lymphoma were excluded. Marked clinical, morphological, and immunologic diversity was observed. Cutaneous lymphoma was found in approximately 50% of the patient group, and 27% had a prior history of dermatologic or immunologic disease. No correlations among immunologic and morphologic phenotypes and clinical course were apparent. Survival data was comparable to that of a concurrent group of non-T cell lymphoma patients studied at this institution, suggesting that, contrary to previous reports, T cell lymphoma may not necessarily confer a more unfavorable prognosis. Prospective studies using uniform treatments are necessary to address the clinical significance of the T cell phenotype definitively, independent of established histologic and clinical features.

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33

Horning, SJ, LM Weiss, GS Crabtree, and RA Warnke. "Clinical and phenotypic diversity of T cell lymphomas." Blood 67, no. 6 (June 1, 1986): 1578–82. http://dx.doi.org/10.1182/blood.v67.6.1578.bloodjournal6761578.

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Forty-one cases of T cell lymphoma were identified on the basis of morphology and the expression of two or more T cell antigens with an absence of B cell markers. Mycosis fungoides and lymphoblastic lymphoma were excluded. Marked clinical, morphological, and immunologic diversity was observed. Cutaneous lymphoma was found in approximately 50% of the patient group, and 27% had a prior history of dermatologic or immunologic disease. No correlations among immunologic and morphologic phenotypes and clinical course were apparent. Survival data was comparable to that of a concurrent group of non-T cell lymphoma patients studied at this institution, suggesting that, contrary to previous reports, T cell lymphoma may not necessarily confer a more unfavorable prognosis. Prospective studies using uniform treatments are necessary to address the clinical significance of the T cell phenotype definitively, independent of established histologic and clinical features.

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34

Park, Seong Hoe. "T-Cell Education in Thymus-Diversity and Selection." Journal of the Korean Medical Association 41, no. 1 (1998): 92. http://dx.doi.org/10.5124/jkma.1998.41.1.92.

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35

Vanhanen, Reetta, Nelli Heikkilä, Kunal Aggarwal, David Hamm, Heikki Tarkkila, Tommi Pätilä, T. Sakari Jokiranta, Jari Saramäki, and T. Petteri Arstila. "T cell receptor diversity in the human thymus." Molecular Immunology 76 (August 2016): 116–22. http://dx.doi.org/10.1016/j.molimm.2016.07.002.

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36

Goronzy, Jörg J., and Cornelia M. Weyand. "T cell development and receptor diversity during aging." Current Opinion in Immunology 17, no. 5 (October 2005): 468–75. http://dx.doi.org/10.1016/j.coi.2005.07.020.

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37

Baum, Paul D., Jennifer J. Young, and Joseph M. McCune. "Measurement of absolute T cell receptor rearrangement diversity." Journal of Immunological Methods 368, no. 1-2 (May 2011): 45–53. http://dx.doi.org/10.1016/j.jim.2011.03.001.

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38

Chang, Cynthia Xin Lei. "Sources of diversity in T cell epitope discovery." Frontiers in Bioscience 16, no. 1 (2011): 3014. http://dx.doi.org/10.2741/3895.

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39

Franckaert, Dean, and Adrian Liston. "Expression Diversity Adds Richness to T Cell Populations." Immunity 45, no. 5 (November 2016): 960–62. http://dx.doi.org/10.1016/j.immuni.2016.10.019.

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40

Eyerman, M. C., X. Zhang, and L. J. Wysocki. "T cell recognition and tolerance of antibody diversity." Journal of Immunology 157, no. 3 (August 1, 1996): 1037–46. http://dx.doi.org/10.4049/jimmunol.157.3.1037.

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Abstract The capacity of B cells to self-present their Ab variable regions in the context of class II MHC structures suggests a potential regulatory problem. If T cells were able to recognize self-presented Ab, then T cell help might be delivered to B cells independently of a foreign carrier epitope, resulting in a chronic state of unregulated Ab synthesis. For this reason, we have proposed that T cells normally attain a state of tolerance to Ab V region diversity. Here, we tested this idea by performing direct immunizations with unmutated isologous mAb. We also identified and analyzed epitopes recognized by class II MHC-restricted T cell hybridomas that were originally generated against two physiologically mutated isologous mAb. Our results indicate that the class II MHC-restricted T cell repertoire is tolerant of germ-line-encoded Ab diversity and that the physiologic somatic hypermutation process creates immunogenic epitopes in Ab V regions, in some cases by producing class II MHC-binding peptides. In agreement with these findings, we found that germ-line-encoded Ab V regions are presented by endogenous splenic APC at a level that is physiologically significant.

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41

Eyerman, M. C., and L. Wysocki. "T cell recognition of somatically-generated Ab diversity." Journal of Immunology 152, no. 4 (February 15, 1994): 1569–77. http://dx.doi.org/10.4049/jimmunol.152.4.1569.

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Abstract During an immune response, specific Abs and B cells that are infrequently represented in the preimmune repertoire become amplified to abundance. Novel structures are also created through the physiological process of somatic hypermutation in Ab genes. This presents a challenge for T cell self-tolerance, because many potential V region epitopes are either rare or nonexistent during the maturation of the T cell repertoire in the thymus. To explore the potential for T cell recognition of Ab V regions, we immunized A/J mice with two somatically mutated mAbs (mAb36-71 and mAb45-49) derived from A/J mice and produced 13 mAb-specific T cell hybridomas. All of the T cell hybridomas express alpha beta receptors and CD4, and their responses to the mAb are restricted in the context of class II MHC glycoproteins. In presentation studies with fixed APCs and whole or trypsinized mAb, we found that processing of the mAb is necessary for stimulation of the T cell hybridomas. Therefore each of the hybridomas recognizes the mAbs in a conventional class II MHC-restricted manner. We also found that each of the 13 T cell hybridomas responded to the somatically-mutated light chains of mAb45-49 and mAb36-71. In contrast, none of them responded to unmutated versions of the same light chains. These results show that the T cell repertoire includes members able to recognize syngeneic Abs containing somatic mutations that were physiologically acquired during the course of an immune response.

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42

Wang, Shiyu, Longlong Wang, Yang Liu, Yonggang Zhu, and Ya Liu. "Characteristics of T-cell receptor repertoire of stem cell-like memory CD4+ T cells." PeerJ 9 (August 25, 2021): e11987. http://dx.doi.org/10.7717/peerj.11987.

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Stem cell-like memory T cells (Tscm) combine phenotypes of naïve and memory. However, it remains unclear how T cell receptor (TCR) characteristics contribute to heterogeneity in Tscm and other memory T cells. We compared the TCR-beta (TRB) repertoire characteristics of CD4+ Tscm with those of naïve and other CD4+ memory (Tm) in 16 human subjects. Compared with Tm, Tscm had an increased diversity across all stretches of TRB repertoire structure, a skewed gene usage, and a shorter length distribution of CDR3 region. These distinctions between Tscm and Tm were enlarged in top1000 abundant clonotypes. Furthermore, top1000 clonotypes in Tscm were more public than those in Tm and grouped in more clusters, implying more epitope types recognized by top1000 clonotypes in Tscm. Importantly, self-reactive clonotypes were public and enriched in Tscm rather than Tm, of type one diabetes patients. Therefore, this study highlights the unique features of Tscm different from those of other memory subsets and provides clues to understand the physiological and pathological functions of Tscm.

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43

Garner, Lucy C., Ali Amini, Michael E. B. FitzPatrick, Martin J. Lett, Gabriel F. Hess, Magdalena Filipowicz Sinnreich, Nicholas M. Provine, and Paul Klenerman. "Single-cell analysis of human MAIT cell transcriptional, functional and clonal diversity." Nature Immunology 24, no. 9 (August 14, 2023): 1565–78. http://dx.doi.org/10.1038/s41590-023-01575-1.

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AbstractMucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.

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44

Jarduli, Luciana Ribeiro, Adriana Aparecida Marques, Julia Teixeira Cottas de Azevedo, Keli Cristina de Lima, Wilson Araújo da Silva Júnior, Dimas Tadeu Covas, Belinda Pinto Simoes, Ana Cristina Silva Pinto, and Kelen Cristina Ribeiro Malmegrim de Farias. "T Cell Repertoire Diversity of Sickle Cell Anemia Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Conventional Treatments." Blood 128, no. 22 (December 2, 2016): 4586. http://dx.doi.org/10.1182/blood.v128.22.4586.4586.

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Abstract Introduction:Sickle cell anemia (SCA) is a hereditary disorder caused by a mutation in the hemoglobin gene that produces an abnormal hemoglobin S (HbS). The polymerization of the HbS in the red cells is a key of SCA pathophysiology, leading to vaso-occlusive crisis, chronic inflammation, infections, organ ischemia and deficiencies (Hebbel, 2011). SCA is a disease with a highly variable phenotype. Clinical manifestations of the each patient and predictors of disease progression might guide therapeutic decisions. Currently, the available treatments for SCA are hydroxyurea (HU), chronic transfusions of red blood cells (RBC) and the allogeneic hematopoietic stem cell transplantation (allo-HSCT). The occurrence of thymic tissue micro-infarctions and its consequence to patient immunity has never been evaluated. A functional thymus ensures the generation of naive T cells and a consequent diverse T-cell repertoire. The generation and maintenance of a diverse T-cell repertoire is a critical element of immune competence. We hypothesized that SCA patients may have thymic dysfunction caused by micro-infarctions of the thymic tissue, leading to defective output of new naïve T cells, decreased diversity of the peripheral T cell repertoire, and altered adaptive immunity. The objective of this study was to evaluate the peripheral T cell repertoire diversity of SCA patients without treatment and under treatment with hydroxyurea, or chronic transfusions, or allogeneic hematopoietic stem transplantation. Methods and Patients: Peripheral blood mononuclear cells were isolated from patients patients with SCA patients without treatment (n= 9) and under treatment with hydroxyurea (n=10), or chronic transfusions (n = 9), or allogeneic hematopoietic stem transplantation (n = 20), and in a group of heath afro-descendants individuals (n = 9). The diversity of the T cell repertoire was evaluated by TCRBV CDR3 Length Spectratyping method, which is based on the amplification of CDR3 region of TCR by two polymerase chain reactions, followed by capillary electrophoresis of CDR3 segments on automated DNA sequencer (ABI 3500xL Genetic Analyzer, Applied Biosystems, Foster City, CA, USA) and analyzed by Gene Mapper™ software (Applied Biosystems, Foster City, CA, USA) (Pannetier et al, 1993). The results were analyzed by the GraphPad Prism 5 software (La Jolla, CA, USA). Values were expressed as mean ± standard error of the mean. The differences were evaluated using analysis of variance (ANOVA) with the Bonferroni posttest orMann-Whitney nonparametric test as appropriate. The results were considered statistically significant when p < 0.05. Results:Our findings demonstrated that patients with SCA have altered T cell repertories. Patients treated with hydroxyurea showed improved diversity of the T-cell repertoire compared to patients without any treatment. In addition, SCA patients treated with allo-HSCT showed a restricted T-cell repertoire diversity before transplantation, which even decreased at three months after transplantation, compared to pre-transplantation score. SCA patients showed an increase in the percentage of T cells expressing Vβ22 at one year and at ≥ 2 years after transplantation. Patients without any treatment showed a more diverse T cell repertoire diversity than patients who underwent allo-HSCT. Therefore, the TCR diversity was lower in SCA patients with more severe clinical manifestations and refractory to other treatments, which were selected to undergo allo-HSCT. Conclusions:Our initial data suggest that patients with SCA might have thymic dysfunction, probably due to micro-infarctions of the thymic tissue by sickled cells. Analyses of the pattern of CDR3 peak distribution for each TCRVβ provided information about the T-cell generation via thymic-dependent pathway in patients with SCA under different kind of treatments. In conclusion, we demonstrated that SCA patients have decreased diversity of their peripheral T cell repertoire, which might affect their adaptive immunity. Further studies are necessary to confirm the peripheral T cell repertoire alterations in SCA patients and to investigate if current treatments are effective to improve thymic function and T cell repertoire diversity in SCA patients. Disclosures No relevant conflicts of interest to declare.

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Le Paslier, D., Z. Chen, P. Loiseau, D. Cohen, and F. Sigaux. "T cell rearranging gene gamma: diversity and mRNA expression in fresh cells from T cell acute lymphoblastic leukemia." Blood 70, no. 3 (September 1, 1987): 637–46. http://dx.doi.org/10.1182/blood.v70.3.637.637.

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Abstract Rearrangement and in most cases expression of the T cell rearranging genes gamma (TRG gamma) and T cell antigen receptor beta chain (TCR beta) genes were studied in 19 cases of T cell acute malignancies where the surface phenotype is representative of the different stages of thymic maturation. TCR alpha gene transcription was also studied. TRG gamma and TCR beta genes were found to be rearranged in all but one case. The TRG gamma rearrangement pattern seen in most cases is compatible with biallelic rearrangement by loop excision involving the J gamma 2 regions. The sizes of all but two rearranged bands were identical to those of the rearranged bands seen in polyclonal T lymphocytes also studied in this work. One identical-sized band was found in 11 of the 18 rearranged cases. The expression of TRG gamma mRNA (transcripts of 1.6 kilobases [kb]) was highly variable from case to case and did not correlate with the stage of differentiation of the malignant cells, the expression of the molecules CD4 and CD8, the expression and size of the transcripts of the TCR beta genes, and the transcription of TCR alpha genes. In one CD3 + case, strong expression of the TRG gamma transcripts coexisted with the exclusive presence of TCR beta mRNA of 1.0 kb. The cells from this case did not react with anti-Ti antibody and exhibited no natural killer activity. These findings are suggestive of a malignancy that may express the recently isolated CD3-TRG gamma complex.

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46

Le Paslier, D., Z. Chen, P. Loiseau, D. Cohen, and F. Sigaux. "T cell rearranging gene gamma: diversity and mRNA expression in fresh cells from T cell acute lymphoblastic leukemia." Blood 70, no. 3 (September 1, 1987): 637–46. http://dx.doi.org/10.1182/blood.v70.3.637.bloodjournal703637.

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Rearrangement and in most cases expression of the T cell rearranging genes gamma (TRG gamma) and T cell antigen receptor beta chain (TCR beta) genes were studied in 19 cases of T cell acute malignancies where the surface phenotype is representative of the different stages of thymic maturation. TCR alpha gene transcription was also studied. TRG gamma and TCR beta genes were found to be rearranged in all but one case. The TRG gamma rearrangement pattern seen in most cases is compatible with biallelic rearrangement by loop excision involving the J gamma 2 regions. The sizes of all but two rearranged bands were identical to those of the rearranged bands seen in polyclonal T lymphocytes also studied in this work. One identical-sized band was found in 11 of the 18 rearranged cases. The expression of TRG gamma mRNA (transcripts of 1.6 kilobases [kb]) was highly variable from case to case and did not correlate with the stage of differentiation of the malignant cells, the expression of the molecules CD4 and CD8, the expression and size of the transcripts of the TCR beta genes, and the transcription of TCR alpha genes. In one CD3 + case, strong expression of the TRG gamma transcripts coexisted with the exclusive presence of TCR beta mRNA of 1.0 kb. The cells from this case did not react with anti-Ti antibody and exhibited no natural killer activity. These findings are suggestive of a malignancy that may express the recently isolated CD3-TRG gamma complex.

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Joao, Cristina M., Brenda M. Ogle, Marilia Cascalho, and Jeffrey L. Platt. "Driving T Cell Development in the Thymus." Blood 104, no. 11 (November 16, 2004): 3860. http://dx.doi.org/10.1182/blood.v104.11.3860.3860.

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Abstract Background: Classic reports on lymphocyte development hold that B and T cells develop independently. This concept derives in part from the observation that patients with pure B cell immunodeficiency and hypogammaglobulinemia have a normal thymus and T cell numbers. Our recent findings however challenge this concept. We found that T cell development depends not only on the interaction of T cell precursors with thymic epithelial cells but also on other cells. Here we report that those other cells are B cells. Aims: The purpose of this study was to determine whether B cells drive T cell development and TCR diversification in the thymus. Methods: We compared the number of sub-populations of thymocytes and TCR repertoire diversity in B-cell deficient and B-cell proficient mice and in B cell deficient mice following immunoglobulin (Ig) injections. Total leucocytes numbers were determined with a Coulter counter and numbers of thymocytes sub-populations were calculated by flow cytometry analysis. TCR repertoire diversity was measured by a novel method based on hybridization of TCR Vβ specific cRNA on a gene chip platform. Results: In B-cell deficient mice the number of thymocytes was four times reduced and TCR Vβ chain diversity was up to one million times lower compared with wild type mice. Numbers and diversity were restored by treatment of the mice with gamma globulin (see table). Conclusions: T cell development and diversification is driven by B cells. Mice Number of total thymocytes (mean ± standard deviation) p Value β V TCR diversity of thymocytes (median; min.-max.) p Value C57BL/6 (wild mice) 1.3 x 108 ± 5.1 x 107N=7 4.7 x 106; 1.0 x 105 − 1.1 x 108N=5 JH−/− (B cell immunodeficient mice) 3.1 x 107 ± 1.7 x107N=7 0.002 5.9 x 102; 3.6 x 102 − 1.1 x 103N=5 0.0002 JH−/− treated with Ig 3.9 x 107 ± 1.4 x106N=2 0.20 1.1 x 105; 2.7 x 100 − 7.7 x 105N=4 0.08

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Sarzotti-Kelsoe, Marcella, Chan M. Win, Roberta E. Parrott, Myriah Cooney, Barry K. Moser, Joseph L. Roberts, Gregory D. Sempowski, and Rebecca H. Buckley. "Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras." Blood 114, no. 7 (August 13, 2009): 1445–53. http://dx.doi.org/10.1182/blood-2009-01-199323.

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Abstract Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.

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Gleason, Laura, Pierluigi Porcu, and Neda Nikbakht. "Reduced Overall T-Cell Receptor Diversity As an Indicator of Aggressive Cutaneous T-Cell Lymphoma." Blood 140, Supplement 1 (November 15, 2022): 3539–40. http://dx.doi.org/10.1182/blood-2022-170357.

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Hsieh, Meng-Ying, Wan-Hsiang Hong, Jainn-Jim Lin, Wen-I. Lee, Kuang-Lin Lin, Huei-Shyong Wang, Shih-Hsiang Chen, Chao-Ping Yang, Tang-Her Jaing, and Jing-Long Huang. "T-cell receptor excision circles and repertoire diversity in children with profound T-cell immunodeficiency." Journal of Microbiology, Immunology and Infection 46, no. 5 (October 2013): 374–81. http://dx.doi.org/10.1016/j.jmii.2012.06.003.

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