Crowl and Hegg et al. used phenotypic, transcriptomic, and epigenomic analyses of CMV-specific (P14) T cells to demonstrate a role of tissue context in the generation and maintenance of critically important tissue-resident memory T cells (TRM). Although some TRM features were shared across tissues and were distinct from blood/spleen T cells, tissue-specific patterns emerged. Intraepithelial lymphocytes from the small intestine showed the greatest distinctions. TGFβ and chemokine axes can be drivers of specificity, and analysis of transcription factors revealed that Hic1 had opposing effects in different tissue contexts.
Contributed by Ed Fritsch
ABSTRACT: Tissue-resident memory T cells (T(RM) cells) provide protective immunity, but the contributions of specific tissue environments to T(RM) cell differentiation and homeostasis are not well understood. In the present study, the diversity of gene expression and genome accessibility by mouse CD8(+) T(RM) cells from distinct organs that responded to viral infection revealed both shared and tissue-specific transcriptional and epigenetic signatures. T(RM) cells in the intestine and salivary glands expressed transforming growth factor (TGF)-_-induced genes and were maintained by ongoing TGF-_ signaling, whereas those in the fat, kidney and liver were not. Constructing transcriptional-regulatory networks identified the transcriptional repressor Hic1 as a critical regulator of T(RM) cell differentiation in the small intestine and showed that Hic1 overexpression enhanced T(RM) cell differentiation and protection from infection. Provision of a framework for understanding how CD8(+) T(RM) cells adapt to distinct tissue environments, and identification of tissue-specific transcriptional regulators mediating these adaptations, inform strategies to boost protective memory responses at sites most vulnerable to infection.