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 (T(H)1)/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 T(H)1/17/regulatory T (T(reg)) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, T(H)1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only T(H)1/17-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 T(H)1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into T(H)1/17/T(reg) cells, with the latter response tonically constrained by preexisting T(reg) cells. Together, our results identify undifferentiated MP CD4(+) T lymphocytes as a unique precursor that has a diverse differentiation potential to generate T(H)1/17/T(reg) cells to contribute to pathogenesis of inflammation.