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

Abstract

Resident memory CD8 T (Trm) cells 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 immune-mediated 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 >1 yr 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 cytokine producers, 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 Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

“…To note, intestinal Mfs do not express CCR7 (135,222,246), suggesting that they cannot migrate to mLNs to interact with naïve T cells in situ. Therefore, given that human intestinal T cells are almost entirely memory T cells (257)(258)(259), the biological significance of the ability of intestinal Mfs to regulate naïve CD4 + T cells as shown ex vivo is not clear.…”

“…To note, Fenton et al recently showed that intestinal cDCs that highly express integrin αVβ8, such as cDC2, but not cDC1, might induce higher Treg polarization through TGF-β secretion (266). Nevertheless, given that there are few naïve CD4 + T cells in human intestinal mucosa (257)(258)(259), it is more relevant to study naïve CD4 + T cell polarization with cDCs from mLNs, as discussed below.…”

The human small intestine contains two subsets of regulatory Foxp3+ CD4+ T cells with very different life span and functional properties

“…Human SI Helios-Tregs, on the other hand, displayed turnover dynamics similar to noncirculating CD4 and CD8 Trm cells (19) (16), and persisted for >1 year in transplanted SI.…”

“…Only patients without clinical and histological signs of rejection were included. This approach provided a unique possibility to study the lifespan of tissue-resident cells directly because there is no recruitment of donor cells from the circulation (16)(17)(18). Because most donors and recipients express different HLA class I molecules, donor and recipient can be readily distinguished by flow cytometry (Fig.…”

“…Because most donors and recipients express different HLA class I molecules, donor and recipient can be readily distinguished by flow cytometry (Fig. 3b) (16)(17)(18). We recently reported that the majority of CD8 and CD4 T cells were still of donor origin 52 weeks after transplantation (16)( (19)).…”