Alterations in the Thymic Selection Threshold Skew the Self-Reactivity of the TCR Repertoire in Neonates

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 a TCR for self-peptide presented by MHC (self-pMHC) impacts T cell function, we sought to determine whether altered thymic selection influences 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 with their adult counterparts, and this difference in self-reactivity was independent of the germline bias of the neonatal 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 conventional and regulatory T cell selection. Importantly, the distinct levels of T cell self-reactivity reflect physiologically relevant differences based on the preferential expansion of T cells from young mice to fill a lymphopenic environment. Therefore, differences in thymic selection in young versus adult mice skew the TCR repertoire, and the relatively higher self-reactivity of the T cell pool may contribute to the distinct immune responses observed in neonates.

Neonatal T Cells: A Reinterpretation

“…However, recent studies have shown that the neonatal TCR repertoire is also biased toward self-reactive TCRs, which has important bearing on how we interpret their functions. Support for a more self-reactive TCR repertoire in neonatal T cells comes from studies done in mice (60) and humans (61) that show higher amounts of CD5, a marker of TCR avidity for self-pMHC molecules, on neonatal T cells compared to their adult counterparts. These findings are significant because the affinity between TCRs and self-pMHC molecules influences their ability to undergo homeostatic proliferation and react to foreign antigens.…”

Dissecting the defects in the neonatal CD8+ T-cell response

“…CD8 + Tregs can be generated extrathymically by parenchymal cells and suppress neonatal CD8 + T cells in transplantation models and persist into adulthood to maintain tolerance . Murine neonatal CD8 + Tregs have increased CD5 surface expression indicating stronger TCR signaling suggesting, there may be a preferential selection for only high affinity TCR clones for single‐positive thymocytes and Treg development . In early murine life (preweaning), antigenic exposure is limited from the gut by microbial induction of epidermal growth factor, which reduces the formation of goblet cell‐associated antigen passages and promotes the development of Tregs.…”

Socioenvironmental stressors encountered during spaceflight partially affect the murine TCR‐β repertoire and increase its self‐reactivity

“…This study revealed that the neonatal repertoire contains self-reactive CDR3 and that the frequency of these CDR3 is higher in the minor repertoire of CUMS pups. Previous studies have demonstrated that the neonatal TCR-b repertoire has cross-reactive properties (29). Wooldridge et al (31) suggested that a high level of receptor degeneracy, enabling each TCR to recognize multiple peptides, developed during evolution.…”