IL-7-dependent and -independent lineages of IL-7R-dependent human T cells

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes but normal blood counts of B and NK cells (T-B+NK+ SCID). We report six adults (aged 22 to 59 years) from four kindreds and three ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency. Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and ILC cells. By contrast, the patients had profound T-cell lymphopenia, with low proportions of innate-like adaptive MAIT and iNKT lymphocytes. They also had low blood counts of T-cell receptor excision circles (TRECs), recent thymic emigrant T cells, and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7 independent homeostatic T-cell proliferation in the periphery. Intriguingly, the proportions of other T-cell subsets, including TCR gamma/delta+ T cells and some TCR alpha/beta + T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T-cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly TSLP, governs an IL-7-independent pathway of human T-cell development.