Local heroes or villains: tissue-resident memory T cells in human health and disease

Abstract

Tissue-resident memory T (T_RM) cells are increasingly associated with the outcomes of health and disease. T_RM cells can mediate local immune protection against infections and cancer, which has led to interest in T_RM cells as targets for vaccination and immunotherapies. However, these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis, alopecia areata, and vitiligo. Here, we summarize the biology of T_RM cells established in animal models and in translational human studies. We review the beneficial effects of T_RM cells in mediating protective responses against infection and cancer and the adverse role of T_RM cells in driving pathology in autoimmunity. A further understanding of the breadth and mechanisms of T_RM cell activity is essential for the safe design of strategies that manipulate T_RM cells, such that protective responses can be enhanced without unwanted tissue damage, and pathogenic T_RM cells can be eliminated without losing local immunity.

Keywords: T cells; human; immunity; memory; tissue-resident.

Fig. 1. Overview of T_RM cell function in human disease.

Human T_RM cells have been isolated from a broad range of tissues and assessed for their associations with disease activity in the context of infection, cancer, autoimmunity and transplantation as summarized here. Infection: Epstein–Barr virus (EBV)-specific T cells have been identified in the tonsils of infected patients and have shown an increased frequency of CD69 and CD103 coexpression compared to their counterparts in the blood and spleen.^– Lung T_RM cells from influenza patients as well as liver T_RM cells from hepatitis B virus (HBV)-infected patients are capable of producing strong levels of IFNγ and TNFα ex vivo, and high numbers of these T_RM cells were found to correlate with reduced disease severity. This was similarly observed for patients infected with respiratory syncytial virus (RSV),^– cytomegalovirus (CMV),^,,–, and hepatitis C virus (HCV), whereby increased T_RM cell numbers were associated with reduced disease activity. A more robust polyfunctional cytokine response by human immunodeficiency virus (HIV)-specific T_RM cells is observed in patients who are able to better control infection.^– While herpes simplex virus (HSV)-specific T_RM cells have shown direct viral control in murine studies,^– it has also been predicted that a higher density of HSV-reactive T_RM cells in humans can correlate with successful viral containment. Cancer: Multiple studies have demonstrated that increased numbers of T_RM cells can correlate with an improved survival rate of patients, including those with oropharyngeal squamous cell carcinoma (OPSCC),^– head and neck squamous cell carcinoma (HNSCC), breast cancer, nonsmall-cell lung cancer (NSCLC), bladder cancer,^, and melanoma. Moreover, T_RM cells with higher levels of perforin, granzyme B, and other effector proteins were noted in cohorts of patients with better disease prognosis.^,, Autoimmunity: The presence of cytokine-secreting T_RM cells in the skin has been shown to be associated with poor outcomes in psoriasis, vitiligo, and alopecia areata (AA). While an increase in IL-17 production has been correlated with psoriasis disease activity, the secretion of IFNγ may be linked to AA disease progression, and the production of perforin and granzyme B may play a role in vitiligo. Transplantation: Studies have described the persistence of donor-derived lymphocytes in allografts of solid organ transplantation. While the correlation of donor-derived T_RM cells in both intestinal^, and lung transplantation has been associated with a reduced incidence of rejection, conflicting studies from facial skin transplant inferred negative outcomes with the use of donor-derived T_RM cells. Therefore, the contribution of T_RM cells to the transplantation field is still in its infancy, and more studies are needed to understand the contribution of donor and recipient cells to allograft rejection.