STAT4 programs CD103− tissue-resident memory cells during infection

Abstract Tissue-resident memory (Trm) CD8+ T cells represent a distinct population of memory T cells that are maintained independently of the circulation and are positioned to respond rapidly to reinfection of the tissue. Using the bacterial pathogen Yersinia pseudotuberculosis (Yptb), we identified two distinct intestinal CD8+ Trm populations that are differentiated by their expression of the integrin CD103. Proximity of T cells to areas of inflammation within the intestinal tissue regulated Trm differentiation, with IL-12 leading to increased numbers of CD103− Trm cells. Therefore, we examined the role of the transcription factor STAT4 in the programming of this Trm subset. During infection, both wild-type and Stat4−/− T cells expanded and entered the intestinal tissue at similar rates. Stat4−/− T cells localized to areas of inflammation along with wild-type cells, but failed to express CD103− Trm signature genes. After infection, Stat4−/− CD103+ intestinal Trm cells formed a stable memory population; however, the number of Stat4−/− CD103− Trm cells was significantly reduced relative to wild-type Trm cells. We also observed impaired persistence of Stat4−/− CD103− Trm cells in other tissues with prominent CD103− Trm populations, including the liver, colon, and mesenteric adipose. RNA-seq analysis of wild-type and Stat4−/− CD103− Trm populations was used to identify genes required for the maintenance of this Trm subset. This work has identified STAT4 as a regulator of CD103− Trm differentiation and maintenance across multiple tissues, and these results will help identify strategies to maximize the number and persistence of Trm cells during vaccination and allow us to address the role of Trm heterogeneity in tissue-specific immunity.