The role of microenvironmental cues in regulating tissue immune surveillance

Abstract

Tissue-resident memory T (TRM) cells provide frontline immune defense against pathogens and malignancies in peripheral tissues. The tissue microenvironment plays a vital role in the development of TRM cells, shaping their abundance, phenotype and function through host-derived factors. Although tissue microenvironments are diverse in nature, they converge to instruct a common tissue-residency program in T cells that promotes local retention while inhibiting tissue-egress pathways. The cytokine transforming growth factor-beta (TGFβ) is a key regulator of TRM cell development. However, in non-epithelial sites such as the liver, TRM cells form through a TGFβ-independent tissue-residency program, which indicates that additional factors have evolved to direct tissue-residency. Beyond the effects of host-derived factors, microenvironmental perturbations such as microbial experience and chronic infections influence TRM cell dynamics, highlighting the need to understand the tissue-derived factors controlling TRM cells.

In this thesis, we examined the contribution of microenvironmental factors in shaping TRM cell development, function and persistence using genetically manipulated CD8+ T cells, multi-omics sequencing methods and a mouse model with increased microbial diversity. We found that TRM cell development across tissue sites was orchestrated by the metabolite retinoic acid (RA) through the receptor RARα. While TRM cell generation in the small intestine epithelium (SI-epithelium), liver and kidney were dependent on the RA-RARα signaling axis, the absence of RA signals induced TRM cell formation in skin and colon. Importantly, SI-epithelium TRM cells could bypass TGFβ dependency by utilizing the RA-induced differentiation pathway.

RA was also critical for the long-term maintenance of SI-epithelium TRM cells, in part by impeding retrograde migration of TRM cells to the mesenteric lymph node (mLN). In contrast, chronic infection led to SI-epithelium TRM cell erosion due to sensing of danger signals via purinergic receptor P2RX7, demonstrating that SI-epithelium TRM cell durability is dynamic.

Further, our results revealed that RA signaling induced TRM cell phenotypic and functional changes, a phenomenon reflected in mice with enhanced microbial diversity. Microbial experience also caused intestinal lengthening accompanied by increased intestinal CD8αβ+ and CD4+ T cells with altered phenotypes, suggesting that microbial diversity enhances tissue-residency and adds layers of TRM cell heterogeneity.

Overall, our findings reveal additional microenvironmental cues that are critical for balancing TRM cell abundance and function across tissues. This research provides a rationale for targeting environmental regulators to modulate TRM cells in a tissue-specific manner for improved immune defenses.