Naturally arising memory-phenotype CD4⁺ T lymphocytes contain an undifferentiated population that can generate T_H1,...

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_H1)/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_H1/17/regulatory T (T_reg) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, T_H1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only T_H1/17-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_H1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into T_H1/17/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_H1/17/T_reg cells to contribute to pathogenesis of inflammation.