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Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions

T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relations...

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Autores principales: Swee, Lee Kim, Tan, Zhen Wei, Sanecka, Anna, Yoshida, Nagisa, Patel, Harshil, Grotenbreg, Gijsbert, Frickel, Eva-Maria, Ploegh, Hidde L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133449/
https://www.ncbi.nlm.nih.gov/pubmed/27881740
http://dx.doi.org/10.1098/rsob.160293
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author Swee, Lee Kim
Tan, Zhen Wei
Sanecka, Anna
Yoshida, Nagisa
Patel, Harshil
Grotenbreg, Gijsbert
Frickel, Eva-Maria
Ploegh, Hidde L.
author_facet Swee, Lee Kim
Tan, Zhen Wei
Sanecka, Anna
Yoshida, Nagisa
Patel, Harshil
Grotenbreg, Gijsbert
Frickel, Eva-Maria
Ploegh, Hidde L.
author_sort Swee, Lee Kim
collection PubMed
description T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2(b) haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L(d)-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii. We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro. Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.
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spelling pubmed-51334492016-12-12 Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions Swee, Lee Kim Tan, Zhen Wei Sanecka, Anna Yoshida, Nagisa Patel, Harshil Grotenbreg, Gijsbert Frickel, Eva-Maria Ploegh, Hidde L. Open Biol Research T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2(b) haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L(d)-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii. We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro. Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds. The Royal Society 2016-11-23 /pmc/articles/PMC5133449/ /pubmed/27881740 http://dx.doi.org/10.1098/rsob.160293 Text en © 2016 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research
Swee, Lee Kim
Tan, Zhen Wei
Sanecka, Anna
Yoshida, Nagisa
Patel, Harshil
Grotenbreg, Gijsbert
Frickel, Eva-Maria
Ploegh, Hidde L.
Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title_full Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title_fullStr Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title_full_unstemmed Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title_short Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions
title_sort peripheral self-reactivity regulates antigen-specific cd8 t-cell responses and cell division under physiological conditions
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133449/
https://www.ncbi.nlm.nih.gov/pubmed/27881740
http://dx.doi.org/10.1098/rsob.160293
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