Naturally arising memory-phenotype CD4 + T lymphocytes contain an undifferentiated population that can generate T H 1, T H 17, and T reg cells.

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.