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


Editor’s summary

Tissue-resident memory T (TRM) cells are long-lasting memory T cells that occupy various tissue niches and play assorted specialized functions. Two important TRM cell subsets in human skin are interferon-γ–producing CD8+ TRM1 cells, which have antiviral and anticancer roles, and interleukin-17–secreting CD8+ TRM17 cells, which participate in antibacterial immunity and wound-healing responses. However, both TRM cell subtypes can also contribute to skin pathologies. Studying mice, Park et al. established that skin TRM1 cells require a different signaling pathway for their differentiation relative to TRM17 cells. TRM17 cells could be selectively ablated by targeting elements of the signaling axis that is involved in TRM1 development. —Seth Thomas Scanlon


Abstract

Skin-resident CD8+ T cells include distinct interferon-γ–producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)–producing (TRM17) 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 TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet–Hobit–IL-15 axis, whereas 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, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.

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