The Role of CD4+ Resident Memory T Cells in Local Immunity in the Mucosal Tissue - Protection Versus Pathology

Abstract

Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (T_EM) cells, central memory T (T_CM) cells, and tissue-resident memory T (T_RM) cells have been identified. The most recently identified subset, T_RM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. T_RM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, T_RM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8⁺ T_RM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4⁺ T_RM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4⁺ T_RM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4⁺ T_RM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4⁺ T_RM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.

Keywords: ATAC-seq; Aspergillus fumigatus; CD4+ resident memory T cells; inducible bronchus-associated lymphoid tissue (iBALT); lung fibrosis; pathogenic T cell.

Figure 1

Distribution of various memory T cells in vivo. There are three types of memory T cells in vivo: (1) central memory T (T_CM) cells, which mainly reside in secondary lymphoid tissues, (2) effector memory T (T_EM) cells, which circulate in the blood, non-lymphatic tissues, and secondary lymphoid tissues, and (3) resident memory T (T_RM) cells, which reside within non-lymphoid tissues. (A) A recent study revealed that CX3CR1^hi CD8⁺ T_EM cells are largely excluded from peripheral tissues after viral infection (9). In case of CD8⁺ T_RM cells, a series of recent studies clearly showed that re-activated CD8⁺ T_RM cells rejoined the circulating pool and proliferated in draining lymph nodes (red arrows). Some T_EM cells move back and forth between the blood vessel and parenchyma. (B) However, whether or not CD4⁺ T_RM cells rejoin the circulating pool and a re-activated in the draining lymph nodes is unclear.

Figure 2

A schematic illustration of the experimental techniques used to identify T_RM cells. (A) Surgical connection of two congenic mice allows them to share blood circulation. (B) In vivo intravascular staining marks circulating T cells through the intravascular injection of an anti-cell surface molecule antibody. (C) In tissue transplantation, donor-derived T cells are detected in the graft after transplantation.

Figure 3

The induction of CD4⁺ T_RM cells with a unique regulome signature. Chronic allergic inflammation with fibrosis of the lung induced by repeated exposure to Aspergillus fumigatus antigen causes the induction of two cell populations, CD103-negative CD4⁺ tissue-resident memory T (T_RM) cells and CD103-positive regulatory T (Treg) cells, which are involved in the pathogenesis of fibrotic responses. Each of these cell populations has its own characteristic regulome. For example, CD103-negative CD4⁺ T_RM cells produce proinflammatory cytokines and show specific peaks of ATAC-Seq in the Th2 cytokine loci (arrows). In contrast, CD103-positive Treg cells show specific peaks of ATC-Seq in the Foxp3 locus (arrows).