Human mucosal tissue-resident memory T cells in health and disease

Abstract

Memory T cells are fundamental to maintain immune surveillance of the human body. During the past decade, it has become apparent that non-recirculating resident memory T cells (TRMs) form a first line memory response in tissues to tackle re-infections. The fact that TRMs are essential for local immunity highlights the therapeutic potential of targeting this population against tumors and infections. However, similar to other immune subsets, TRMs are heterogenous and may form distinct effector populations with unique functions at diverse tissue sites. Further insight into the mechanisms of how TRM function and respond to pathogens and malignancies at different mucosal sites will help to shape future vaccine and immunotherapeutic approaches. Here, we review the current understanding of TRM function and biology at four major mucosal sites: gastrointestinal tract, lung, head and neck, as well as female reproductive tract. We also summarize our current knowledge of how TRM targets invading pathogens and developing tumor cells at these mucosal sites and contemplate how TRMs may be exploited to protect from infections and cancer.

Fig. 1. CD8 + TRMs in infections.

TRMs are found in mucosal tissues following different infections. They are known to express variable levels of the tissue retention markers CD69 and CD103. Following IAV infection CD8 + TRMs infiltrate the lung epithelium and induce cell death in the targeted cells through perforin/granzyme delivery as well asl FasL/Fas pathways and produce IFNγ, TNF, IL-2, and other cytokines and chemokines to enhance inflammation and immune activation in the infected lung tissue. HIV-specific CD8 + TRMs express CD69 and intermediate levels of CD103 in the gut mucosal epithelium, where they secrete granzyme A, IFNγ and TNF against HIV-infected cells. In the tonsil, EBV-specific CD8 + TRMs localize at the lymphoepithelial barrier, where most EBV + B cells are found. Tonsillar EBV-specific CD8 + TRMs are polyfunctional and produce IFN-γ among other cytokines. After intravaginal infections HSV-specific CD8 + TRMs are established in the lower FRT, where they persist in the dermo-epidermal junction and rely on perforin/granzyme and cytokine secretion (mostly IFNγ, but also TNF and RANTES expression) for clearance of infected cells.

Fig. 2. CD8 + TRMs in cancer.

TRMs expressing CD103 and CD69 have been identified in numerous cancerous tissues. The presence of TRMs within and around tumor tissues are often associated with improved patient outcomes. Their favorable positioning within the tissues makes TRMs rapid first-line effectors that may suppress and eliminate local tumor growths. In an MHC-I dependent fashion, TRMs can directly lyse tumor cells via release of cytotoxic molecules, such as granzyme B and perforin. Alternatively, TRMs may also influence the local tumor microenvironment (TME) through their enhanced expression of inflammatory cytokines i.e., IFNγ, TNF and IL-2. Expression of inhibitory receptors such as PD-1, CTLA-4, LAG-3, TIM-3 and TIGIT have also found to be elevated on TRMs making them attractive targets for checkpoint blockade therapies. Indeed, tumor-specific TRMs targeted by anti-PD-1 show enhanced reactivity toward autologous tumor samples. Local signals within the TME such as TGF-b or VCAM-1 signaling may also shape TRMs phenotype and survival by influencing TRM markers such as CD103, thus improving retention within tumor tissues.