Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells (Q5648)

Skin-resident CD8+ T cells comprise distinct IFN-γ- (TRM1) and IL-17-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations employ common mechanisms to establish tissue residence is unknown. Here, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in skin. While TRM1 cells depend on a T-bet-Hobit-IL-15 axis, TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, targeting this pathway enables ablation of skin TRM17 cells without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.