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Effector V?9V?2 T cells dominate the human fetal ?? T-cell repertoire.

ABSTRACT: ?? T cells are unconventional T cells recognizing antigens via their ?? T-cell receptor (TCR) in a way that is fundamentally different from conventional ?? T cells. ?? T cells usually are divided into subsets according the type of V? and/or V? chain they express in their TCR. T cells expressing the TCR containing the ?-chain variable region 9 and the ?-chain variable region 2 (V?9V?2 T cells) are the predominant ?? T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, V?9V?2 T cells are the predominant blood subset in the second-trimester fetus, whereas V?1(+) and V?3(+) ?? T cells are present only at low frequencies at this gestational time. Fetal blood V?9V?2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the V?9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3?2. Furthermore, these fetal blood V?9V?2 T cells are functionally preprogrammed (e.g., IFN-? and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine ?? T cells than is usually articulated.

SUBMITTER: Dimova T

PROVIDER: S-EPMC4330771 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire.

Dimova Tanya T Brouwer Margreet M Gosselin Françoise F Tassignon Joël J Leo Oberdan O Donner Catherine C Marchant Arnaud A Vermijlen David D

Proceedings of the National Academy of Sciences of the United States of America 20150123 6

γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this p ...[more]

PMID: 25617367

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Project description:IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is a serious threat to human health. Vaccination with BCG prevents the development of the most severe forms of TB disease in infants and was recently shown to prevent Mtb infection in previously uninfected adolescents. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. However, our understanding of the effects of BCG vaccination on γδ T cell responses is incomplete.MethodsIn this study we performed γδ T cell receptor (TCR) repertoire sequencing of samples provided pre- and post-BCG vaccination from 10 individuals to identify specific receptors and TCR clones that are induced by BCG.ResultsOverall, there was no change in the diversity of γTCR or δTCR clonotypes in post- vs pre-BCG samples. Furthermore, the frequencies of TCR variable and joining region genes were minimally modulated by BCG vaccination at either the γTCR or δTCR loci. However, the γTCR and δTCR repertoires of individuals were highly dynamic; a median of ~1% of γTCR and ~6% of δTCR in the repertoire were found to significantly expand or contract in post- vs pre-BCG comparisons (FDR-q < 0.05). While many of the clonotypes whose frequency changed after BCG vaccination were not shared among multiple individuals in the cohort, several shared (i.e., "public") clonotypes were identified with a consistent increase or decrease in frequency across more than one individual; the degree of sharing of these clonotypes was significantly greater than the minimal sharing that would be expected among γTCR and δTCR repertoires. An in vitro analysis of Mtb antigen-reactive γδ T cells identified clonotypes that were similar or identical to the single-chain γTCRs and δTCRs that changed consistently after BCG vaccination; pairings of γTCRs and δTCRs that increased after BCG vaccination were significantly over-represented among the Mtb-reactive γδ T cells (p = 1.2e-6).DiscussionThese findings generate hypotheses about specific γδTCR clonotypes that may expand in response to BCG vaccination and may recognize Mtb antigens. Future studies are required to validate and characterize these clonotypes, with an aim to better understand the role of γδ T cells in Mtb immunity.

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Effector V?9V?2 T cells dominate the human fetal ?? T-cell repertoire.

Publications

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire.

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