Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted

Abstract

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRMcells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRMtranscriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRMcell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRMpopulations were spatially segregated: with more effector- and memory-like TRMpreferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRMdifferentiation and functional diversity, including different TGFβ sources. Alterations in the cellular networks induced by loss of TGFβRII expression revealed a model consistent with TGFβ promoting progressive TRMmaturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.