Divergent molecular networks program functionally distinct CD8<sup>+</sup>skin-resident memory T cells
Simone L. Park, Susan N. Christo, Alexandria Wells, Luke C. Gandolfo, Ali Zaid, Yannick O. Alexandre, Thomas N. Burn, Jan Schröder, Nicholas Collins, Seong‐Ji Han, Stéphane M. Guillaume, Maximilien Evrard, Clara Castellucci, Brooke Davies, Maleika Osman, Andreas Obers, Keely M. McDonald, Huimeng Wang, Scott N. Mueller, George Kannourakis, Stuart P. Berzins, Lisa A. Mielke, Francis R. Carbone, Axel Kallies, Terence P. Speed, Yasmine Belkaid, Laura K. Mackay
Abstract
Skin-resident CD8 + T cells include distinct interferon-γ–producing [tissue-resident memory T type 1 (T RM 1)] and interleukin-17 (IL-17)–producing (T RM 17) 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 RM 1 and T RM 17 cells navigate divergent trajectories to acquire tissue residency in the skin. T RM 1 cells depend on a T-bet–Hobit–IL-15 axis, whereas T RM 17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T RM 17 cells parallel to that induced by Hobit in T RM 1 cells, with an ICOS–c-Maf–IL-7 axis pivotal to T RM 17 cell commitment. Accordingly, by targeting this pathway, skin T RM 17 cells can be ablated without compromising their T RM 1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.