Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

T‐cell division is central to maintaining a stable T‐cell pool in adults. It also enables T‐cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T‐cell survival in lymphoreplete settings, IL‐7 and T‐cell receptor (TCR) interactions with self‐peptide MHC (pMHC), induce division when T‐cell numbers are low. The strength of reactivity for self‐pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia‐induced proliferation (LIP), in that weakly self‐reactive T cells are unable to divide, implying that T‐cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self‐reactivity and thus compromise T‐cell diversity. Here, we show that while CD4⁺ T cells with low self‐pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4⁺ T cells with low self‐pMHC reactivity are able to contribute to the reconstitution of the T‐cell pool.