Resident memory CD8 T cells persist for years in human small intestine

Abstract

In human small intestine, most CD8 T cells in the lamina propria and epithelium express a resident memory (Trm) phenotype and persist for at least one year in transplanted tissue.Intestinal CD8 Trm cells have a clonally expanded immune repertoire that is stable over time and exhibit enhanced protective capabilities. 2 Graphical abstract: Highlights  The vast majority of CD8 T cells in the human small intestine are Trm cells  CD8 Trm cells persist for >1 year in transplanted duodenum  Intraepithelial and lamina propria CD8 Trm cells show highly similar TCR repertoire  Intestinal CD8 Trm cells efficiently produce cytokines and cytotoxic mediators 3 Abbreviations: IE, intraepithelial LP, lamina propria RPMI, Roswell Park Memorial Institute medium SI, small intestine TCR, T cell receptor Trm, resident memory T cell Tx, pancreatic-duodenal transplantation (of diabetes mellitus patients) Summary: Resident memory CD8 T cells (Trm) have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immunemediated diseases and vaccine development. Analyzing normal and transplanted human SI we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for over 1 year in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokineproducers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets

“…Therefore, additional phenotypic markers to identify CD103 À T RM populations are required. Recent work has exploited the human model of organ transplantation to study long-lived, donor-derived T cells, which are definitively functionally resident T RM cells (Bartolomé -Casado et al, 2019;Snyder et al, 2019;Zuber et al, 2016). Studies using this approach have demonstrated persistence of clonally identical intestinal CD8 + T RM cells for up to 1 year in the small intestine (SI) (Bartolomé -Casado et al, 2019), and persistency of donor-derived T cells for 600 days after transplant (Zuber et al, 2016).…”

“…Recent work has exploited the human model of organ transplantation to study long-lived, donor-derived T cells, which are definitively functionally resident T RM cells (Bartolomé -Casado et al, 2019;Snyder et al, 2019;Zuber et al, 2016). Studies using this approach have demonstrated persistence of clonally identical intestinal CD8 + T RM cells for up to 1 year in the small intestine (SI) (Bartolomé -Casado et al, 2019), and persistency of donor-derived T cells for 600 days after transplant (Zuber et al, 2016). This approach was also used to identify putative SI CD8 + T RM cell subsets based on expression of CD103 and KLRG1, with differences in clonality, granzyme expression, and cytokine production (Bartolomé -Casado et al, 2019).…”

The identity of human tissue-emigrant CD8+T cells

“…The protection afforded by TRM cells is thought to involve via the perforin-mediated transfer of serine proteases, cytolytic activity (Masopust et al, 2001), because many murine TRM cells constitutively express granzyme B (GzmB) (Masopust et al, 2006). However, this paradigm does not necessarily apply to all human TRM cells (Bartolome-Casado et al, 2019;Pallett et al, 2017), which instead exhibit a unique transcriptional profile compared to circulating cells (Kumar et al, 2017) and are thought to work partly as innate-like sensors (Schenkel et al, 2013). As such, it remains an open question of whether human CD8 + T cells with cytolytic molecule expression are constantly surveying tissues and recirculate or merely are restricted to the vasculature at steadystate.…”

Tissue‐resident CD8+T memory cells with unique properties are present in human decidua during early pregnancy

“…Of note, activation and exhaustion‐related molecule PD‐1 prominently highly expressed on decidual T RM cells. Presence of PD‐1 on the majority of CD8 + T RM cells has been described in other tissues, including skin, small intestine, kidney, and brain 6‐9,37 . It may be a general characteristic of the transcriptional program of T RM cells.…”

“…Tissue‐resident memory T (T RM ) cells are a group of memory T cells that are restricted to non‐lymphoid tissues and act as peripheral tissue sentinels that orchestrate the response to pathogens (re)encountered with tissue reinfection. T RM cells have been reported in many tissues, such as skin, small intestine, kidney, brain, vaginal mucosa, and endometrium 6‐13 . T RM cells isolated from different tissues have divergent phenotypic characteristics, but they share a common core transcriptional signature that distinguishes from effector‐memory and central‐memory T cells.…”