Abstract
Deletion of the gene for Themis affects T cell selection in the thymus, which would be expected to affect the TCR repertoire. We found an increased proportion of cells expressing Vα3.2 (TRAV9N-3) in the peripheral CD8+ T cell population in mice with germline Themis deficiency. Analysis of the TCRα repertoire indicated it was generally reduced in diversity in the absence of Themis, whereas the diversity of sequences using the TRAV9N-3 V-region element was increased. In wild type mice, Vα3.2+ cells showed higher CD5, CD6 and CD44 expression than non-Vα3-expressing cells, and this was more marked in cells from Themis-deficient mice. This suggested a virtual memory phenotype, as well as a stronger response to self-pMHC. The Vα3.2+ cells responded more strongly to IL-15, as well as showing bystander effector capability in a Listeria infection. Thus, the unusually large population of Vα3.2+ CD8+ T cells found in the periphery of Themis-deficient mice reflects not only altered thymic selection, but also allowed identification of a subset of bystander-competent cells that are also present in wild-type mice.
Highlights
The inability to predict the foreign antigens that an organism will encounter in its lifetime creates a need for the immune system to generate and maintain a diverse T cell receptor repertoire [1,2,3]
Because Themis regulates thymocyte selection thresholds [39, 42], we predicted that Themis germline deletion would lead to changes in T cell receptor (TCR) repertoire
CD8 SP thymocytes (Figures 3C, D). These results suggest that Va3.2+ cells receive stronger signal from self peptide MHC (pMHC) during development in the thymus, corroborating the findings from the conditional Themis deletion models, where the increased proportion of Va3.2-expressing cells occurred if knockout happened before selection (CD4-Cre), but not if it occurred after selection (Figures 1F, H)
Summary
The inability to predict the foreign antigens that an organism will encounter in its lifetime creates a need for the immune system to generate and maintain a diverse T cell receptor repertoire [1,2,3]. T cells develop in the thymus, where they rearrange T cell receptor (TCR) a and b genes and undergo positive and negative selection to ensure that only cells expressing TCRs which give an optimum response to the self-peptide MHC (pMHC) are allowed to leave the thymus. The TCR is formed by rearrangement of V(D)J elements, such that the binding site for the peptide MHC complex is formed from 3 complementarity determining regions (CDR1, 2, and 3) [4]. Altered Thymic Selection in Themis-Deficient Mice segments have preferences for binding to, and being preferentially selected by, either MHC-I or MHC-II. This selection bias is dictated by their CDR1 and CDR2 sequences [5,6,7] and can affect the CD4+:CD8+ ratio [8]. Structural analysis of TCR-pMHC complexes indicates conserved sites in TCR CDR1 and 2 of Va and Vb that correspond to sites on the MHC a-helices [9], which can explain these biases of selection
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