Clonal Deletion Prunes but Does Not Eliminate Self-Specific αβ CD8+ T Lymphocytes

Yu, Wei; Jiang, Ning; Ebert, Peter; Kidd, Brian; Müller, Sabina; Lund, Peder J.; Juang, Jyuhn‐Huarng; Adachi, Keishi; Tse, Tiffany; Birnbaum, Michael E.; Newell, Evan W.; Wilson, Darrell M.; Grotenbreg, Gijsbert M.; Valitutti, Salvatore; Quake, Stephen R.; Davis, Mark M.

doi:10.1016/j.immuni.2015.05.001

Cited by 253 publications

(259 citation statements)

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“…Along this line, thymic expression of mRNA encoding for MelanA has been previously reported [25,26], although this mRNA might be in most cases truncated, precluding expression of the MelA peptide [27]. The preferential selection of the corresponding Ag-specific T-cell subsets in A2 + donors might thus result from TCR engagement by relevant or closely related p-A2 complexes expressed at densities low enough in the thymus to avoid T-cell deletion [28,29]. Nevertheless, as the hierarchy of recognition also correlates with the efficacy of thymic selection in A2 − donors, it is also tempting to speculate that frequently recognized complexes, like MelA-A2 and PGT-A2, are more structurally related to a conserved p-MHC topology found in the thymic microenvironment of both A2 + and A2 − donors, than less frequently recognized complexes, like pp65-A2 and Gag-A2.…”

Section: Quantitative Impact Of the Expression Of The Mhc Class I-resmentioning

confidence: 98%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHCrestricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2 + donors reacted to A2 + cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. Keywords: Antigen r Human T cells r MHC r Tetramers r Thymocytes See accompanying Commentary by Ciucci and BosselutAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe thymus generates a highly diverse T-cell repertoire able to recognize virtually any antigen that could be encountered by a given individual along his/her life. This diversity is achieved through two main mechanisms. First by the acquisition by CD4 + CD8 + double-positive (DP) thymocytes of a clonally distributed T cell receptor (TCR) that is generated after somatic recombination of TCR V(D)J gene segments and nontemplated nucleotide Correspondence: Dr. Xavier Saulquin e-mail: xavier.saulquin@univ-nantes.fradditions. This quasi-random mechanism allows for the generation of up to 10 15 different receptors [1]. Second, by the shaping of this initial T-cell repertoire by positive and negative thymic selection processes that will favor emergence of a self major histocompatibility molecules (MHC)-restricted, yet self-tolerant, TCR repertoire carried by mature naïve single-positive (SP) T cells. As a consequence of this maturation process, the diversity of SP αβ T cells in a given individual falls in the range of 10 6 to 10 8 [2]. * LH and FL equally contributed to this work. The respective contributions of positive and negative thymic selection processes to the generation of a mature T-cell repertoire possibly biased towards recognition of peptides restricted by host MHC alleles are still debated. Indeed, this phenomenon referred to as "host or Self-MHC-restriction" is a consequence of a balance between (i) the need for a thymocyte to get survival signals from TCR upon interactions of weak/intermediate avidi...

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Section: Quantitative Impact Of the Expression Of The Mhc Class I-resmentioning

confidence: 98%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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“…However, Yu and colleagues recently reported that clonal deletion prunes the Tcell repertoire without fully eliminating self-reactive T cell clones. 18 Thus, self-reactive T cells that survive thymic selection (including CCL22-specific T cells) may actively participate in immune regulation. We recently reported the frequent detection of self-reactive pro-inflammatory T cells that recognize regulatory immune cells, which apparently have a function that counteracts the immune-suppressive feedback signals in the immune system.…”

Section: Pccl22 3-12 Stimulation Decreased the Ccl22 Levels In The MImentioning

confidence: 99%

CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment

et al. 2016

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Tumor cells and tumor-infiltrating macrophages produce the chemokine CCL22, which attracts regulatory T cells (Tregs) into the tumor microenvironment, decreasing anticancer immunity. Here, we investigated the possibility of targeting CCL22-expressing cells by activating specific T cells. We analyzed the CCL22 protein signal sequence, identifying a human leukocyte antigen A2-(HLA-A2-) restricted peptide epitope, which we then used to stimulate peripheral blood mononuclear cells (PMBCs) to expand populations of CCL22-specific T cells in vitro. T cells recognizing an epitope derived from the signal-peptide of CCL22 will recognize CCL22-expressing cells even though CCL22 is secreted out of the cell. CCL22-specific T cells recognized and killed CCL22-expressing cancer cells. Furthermore, CCL22-specific T cells lysed acute monocytic leukemia cells in a CCL22 expression-dependent manner. Using the Enzyme-Linked ImmunoSPOT assay, we examined peripheral blood mononuclear cells from HLA-A2+ cancer patients and healthy volunteers for reactivity against the CCL22-derived T-cell epitope. This revealed spontaneous T-cell responses against the CCL22-derived epitope in cancer patients and in healthy donors. Finally, we performed tetramer enrichment/depletion experiments to examine the impact of HLA-A2-restricted CCL22-specific T cells on CCL22 levels among PMBCs. The addition or activation of CCL22-specific T cells decreased the CCL22 level in the microenvironment. Activating CCL22-specific T cells (e.g., by vaccination) may directly target cancer cells and tumor-associated macrophages, thereby modulating Treg recruitment into the tumor environment and augmenting anticancer immunity.

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“…A number of studies have shown that self-antigen or tumor antigen-specific CD4 + and CD8 + T cells are present in healthy individuals [1][2][3][4]. How such self-or tumor-reactive T cells are controlled in healthy or tumor-bearing individuals remains to be determined.…”

Section: Introductionmentioning

confidence: 99%