Total Recall: Intestinal TRM Cells in Health and Disease

Abstract

Tissue-resident memory T cells (T_RM cells) have crucial functions in host defense in mucosal tissues. They provide local adaptive immune surveillance and allow the fast initiation of targeted adaptive immune responses in case of antigen re-exposure. Recently, an aberrant activation in the case of immunologically mediated diseases has been increasingly acknowledged. As the organ with the largest interface to the environment, the gastrointestinal tract faces billions of antigens every day. Tightly balanced processes are necessary to ensure tolerance towards non-hazardous antigens, but to set up a powerful immune response against potentially dangerous ones. In this complex nexus of immune cells and their mediators, T_RM cells play a central role and have been shown to promote both physiological and pathological events. In this review, we will summarize the current knowledge on the homeostatic functions of T_RM cells and delineate their implication in infection control in the gut. Moreover, we will outline their commitment in immune dysregulation in gastrointestinal chronic inflammatory conditions and shed light on T_RM cells as current and potential future therapeutic targets.

Keywords: infection control; inflammatory bowel diseases; intestine; therapeutic targets; tissue-resident memory T cells.

Figure 1

Profile and function of T_RM cells. Left side: T_RM cells develop during primary infection. The differentiation and maintenance of T_RM cells is controlled by tissue-derived signals, e.g., TNF-α, TGF-β or IL-15 and IL-33 resulting in the up- and down-regulation of different genes via activity of the transcription factors Hobit, Blimp-1, Runx3, and Notch and the silencing of Klf2. In particular, upregulation of CD69 and CD103 and simultaneous downregulation of S1PR1 are key drivers of T_RM cell tissue retention. Other membrane molecules highly expressed in T_RM cells are CD49a, CD101, PD-1, CRTAM, and CXCR6 while CD62L, CCR7, and CX3CR1 show a decreased expression pattern in T_RM cells. Right side: After re-exposure to a cognate antigen (e.g., from a pathogen, shown in purple), T_RM cells are able to initiate a fast immune response. This includes chemokine release to recruit lymphocytes (indicated as red, orange, and blue immune cells) to the site of infection, release of pro-inflammatory cytokines (IFN-γ, TNF-α) to activate other cells as well as the production of the cytotoxic effectors perforin or granzyme B. There is also evidence for the ability of T_RM cells to proliferate or to re-differentiate (indicated as green and orange cells) and to leave the tissue (orange ex-T_RM cells; for details cf. main text). T_RM, tissue-resident memory T cell; TNF, tumor necrosis factor; TGF, transforming growth factor; IL, Interleukin; KLF, Krüppel-like factor; CD, cluster of differentiation; S1PR1, sphingosine-1-phosphate receptor 1; PD-1, programmed cell death protein 1; CRTAM, cytotoxic and regulatory T-cell molecule; CXCR, CXC-motif chemokine receptor; CCR, Chemokine receptor.