Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8⁺ tissue-resident memory T cells

Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8⁺ tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos^−/− CD8⁺ T cells exhibited defective Trm generation but produced recirculating memory populations normally. ICOS deficiency or ICOS-L blockade compromised establishment of CD8⁺ Trm cells but not their maintenance. ICOS ligation during CD8⁺ T cell priming did not determine Trm induction; rather, effector CD8⁺ T cells showed reduced Trm differentiation after seeding into Icosl^−/− mice. Icos^YF/YF CD8⁺ T cells were compromised in Trm generation, indicating a critical role for PI3K signaling. Modest transcriptional changes in the few Icos^−/− Trm cells suggest that ICOS-PI3K signaling primarily enhances the efficiency of CD8⁺ T cell tissue residency. Thus, local ICOS signaling promotes production of Trm cells, providing insight into the contribution of costimulatory signals in the generation of tissue-resident populations.