CD4⁺ T cell effector commitment coupled to self-renewal by asymmetric cell divisions

Upon infection, an activated CD4⁺ T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4⁺ T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TC F1. After four or five divisions, some cells silenced, whereas some cells maintained TC F1 expression. TC F1- silenced cells were T helper 1-like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TC F1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TC F1-silenced daughter cell as well as a sibling cell maintaining TC F1 expression. Some TC F1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4⁺ effector T cells during clonal selection.