Alterations in the thymic selection threshold skew the self-reactivity of the T cell receptor repertoire in neonates

Abstract

Abstract Neonatal and adult T cells differ in their effector functions. Although it is known that cell-intrinsic differences in mature T cells contribute to this phenomenon, the factors involved remain unclear. Given emerging evidence that the binding strength of the TCR for self-peptide presented by MHC (self-pMHC) impacts T cell function, we sought to determine if altered thymic selection thresholds influence the self-reactivity of the TCR repertoire during ontogeny. We found that conventional and regulatory T cell subsets in the thymus of neonates and young mice expressed higher levels of cell-surface CD5, a surrogate marker for TCR avidity for self-pMHC, as compared to their adult counterparts and that this difference in self-reactivity was independent of their distinct TCR repertoire. The increased binding strength of the TCR repertoire for self-pMHC in neonates was not solely due to reported defects in clonal deletion. Rather, our data suggest that thymic selection is altered in young mice such that thymocytes bearing TCRs with low affinity for self-peptide are not efficiently selected into the neonatal repertoire and stronger TCR signals accompany both positive and agonist selection. Importantly, the differences in CD5 levels reflect physiologically relevant differences based on the preferential expansion of T cells from young mice to fill a lymphopenic environment. Therefore, differences in the thymic selection threshold in young versus adult mice skews the TCR repertoire, and the relatively higher self-reactivity of the T cell pool may contribute to the distinct immune responses observed in neonates.