Classic costimulatory interactions in MAIT cell responses: from gene expression to immune regulation

Abstract

Summary Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviours of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumour necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells’ development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…Co‐stimulatory signals collaborate with MHC–antigen–TCR complexes to augment the activation of T cells. Among them, CD28 is crucial in the immune response of T cells 69,70 . After the activation of CD28, phosphatidylinositol‐3‐hydroxykinase/Akt (PI3K/Akt) and other signals are induced to facilitate the proliferation and development of Tn.…”

“…Among them, CD28 is crucial in the immune response of T cells. 69,70 After the activation of CD28, phosphatidylinositol-3-hydroxykinase/ Akt (PI3K/Akt) and other signals are induced to facilitate the proliferation and development of Tn. As a result, Tn-TSCM-TCM-TEM-TTE forms the initial immune response and memory immune response, which allows the body to combat both the "old" antigens produced by tumor recurrence and the "new" ones generated by tumor variation.…”

Current Perspectives and Challenges of MAIT Cell-Directed Therapy for Tuberculosis Infection

“…They play a role in the maturation of dendritic cells, the transactivation and cytotoxicity of natural killer cells [24], the reactivation and differentiation of memory B cells [25], the suppression of innate lymphoid cell proliferation [26], and the regulation of the Th1 response [27]. MAIT cell response is also mediated by costimulatory molecules of the immunoglobulin and TNF superfamilies, which is reviewed in detail by [28]. These cells are enriched in barrier tissues, locations that are most likely to come into first contact with pathogens and thus to incur a rapid inflammatory response that can cause tissue damage.…”

Natural Killer T Cell Diversity and Immunotherapy

“…Their role in infectious diseases, along with their antibacterial and antifungal effects, has been reported [39,40]. Once active, MAIT cells produce cytotoxic substances in order to counteract pathogens, similar to NK cells [41][42][43], and they participate in tissue repair to procure homeostasis [44][45][46] and mount strong cytokine responses, consequently affecting the involvement and functions of other immune cells [47,48]. Nonetheless, unchecked activation of MAIT cells, which may also be achieved by IL-2, IL-12, and IL-18 stimulation, can potentiate diverse adverse effects, such as cytokine storms [49], tissue fibrosis [50], and tumor cell metastasis, among others [51,52].…”