Divergent molecular networks program functionally distinct CD8⁺ skin-resident memory T cells

Skin-resident CD8⁺ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T_RM1)] and interleukin-17 (IL-17)-producing (T_RM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T_RM1 and T_RM17 cells navigate divergent trajectories to acquire tissue residency in the skin. T_RM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas T_RM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T_RM17 cells parallel to that induced by Hobit in T_RM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to T_RM17 cell commitment. Accordingly, by targeting this pathway, skin T_RM17 cells can be ablated without compromising their T_RM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.