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RRAS2 shapes the TCR repertoire by setting the threshold for negative selection.

ABSTRACT: Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2^-/- mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2^-/- mice have reduced affinity for MOG/I-A^b tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2^-/- mice, suggesting their involvement in autoimmunity.

SUBMITTER: Martinez-Riano A

PROVIDER: S-EPMC6781009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2021-02-01 | GSE164895 | GEO

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Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for beta-selection and TCR repertoire formation.

Project description:The pre-T-cell receptor (TCR) is crucial for the early T-cell development, but the ligand for pre-TCR remains unidentified. We recently proposed a model that pre-TCR complexes oligomerize spontaneously through interactions of the pre-TCR? chain. To investigate the mechanism underlying this ligand-independent signaling in vivo, we established knock-in mice that express a pre-TCR? mutant lacking charged amino acids (D(22)R(24)R(102)R(117) to A(22)A(24)A(102)A(117); 4A). CD4(+)CD8(+) thymocyte number was significantly reduced in invariant pre-TCR? (pT?(4A/4A)) mice, whereas CD4(-)CD8(-) thymocytes were unaffected. The percentages of double-negative 3 (DN3) cells and ?? T cells were increased in the pT?(4A/4A) thymus, indicating that ?-selection is impaired in pT?(4A/4A) mice. Pre-TCR-mediated tyrosine phosphorylation and clonal expansion into double-positive thymocytes were also defective in the knock-in mice. Pre-TCR was expressed at higher levels on pT?(4A/4A) cell surfaces than on those of the wild type, suggesting that the charged residues in pT? are critical for autonomous engagement and subsequent internalization of pre-TCR. Pre-TCR-mediated allelic exclusion of the TCR? gene was also inhibited in pT?(4A/4A) mice, and thereby, dual TCR?s were expressed on pT?(4A/4A) T cells. Furthermore, the TCR? chain variable region (V?) repertoire of mature T cells was significantly altered in pT?(4A/4A) mice. These results suggest that charged residues of pT? are critical for ?-selection, allelic exclusion, and TCR? repertoire formation.

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