Naturally arising memory-phenotype CD4+ T lymphocytes contain an undifferentiated population that can generate TH1, TH17, and Treg cells

Abstract

Memory-phenotype (MP) CD4+ T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (TH1)/17–like subsets, functional significance of the T-bet− Rorγt− subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into TH1/17/regulatory T (Treg) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, TH1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only TH1/17-differentiated subsets but a polyclonal, transcriptomically immature “undifferentiated” subpopulation at homeostasis. Furthermore, our data argue that while the T-bet+ Rorγt− MP subset is terminally TH1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into TH1/17/Treg cells, with the latter response tonically constrained by preexisting Treg cells. Together, our results identify undifferentiated MP CD4+ T lymphocytes as a unique precursor that has a diverse differentiation potential to generate TH1/17/Treg cells to contribute to pathogenesis of inflammation.