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 (T1)] and interleukin-17 (IL-17)-producing (T17) 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 T1 and T17 cells navigate divergent trajectories to acquire tissue residency in the skin. T1 cells depend on a T-bet-Hobit-IL-15 axis, whereas T17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T17 cells parallel to that induced by Hobit in T1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to T17 cell commitment. Accordingly, by targeting this pathway, skin T17 cells can be ablated without compromising their T1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.