Insights Into Mucosal-Associated Invariant T Cell Biology From Studies of Invariant Natural Killer T Cells

Abstract

Mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells are innate-like T cells that function at the interface between innate and adaptive immunity. They express semi-invariant T cell receptors (TCRs) and recognize unconventional non-peptide ligands bound to the MHC Class I-like molecules MR1 and CD1d, respectively. MAIT cells and iNKT cells exhibit an effector-memory phenotype and are enriched within the liver and at mucosal sites. In humans, MAIT cell frequencies dwarf those of iNKT cells, while in laboratory mouse strains the opposite is true. Upon activation via TCR- or cytokine-dependent pathways, MAIT cells and iNKT cells rapidly produce cytokines and show direct cytotoxic activity. Consequently, they are essential for effective immunity, and alterations in their frequency and function are associated with numerous infectious, inflammatory, and malignant diseases. Due to their abundance in mice and the earlier development of reagents, iNKT cells have been more extensively studied than MAIT cells. This has led to the routine use of iNKT cells as a reference population for the study of MAIT cells, and such an approach has proven very fruitful. However, MAIT cells and iNKT cells show important phenotypic, functional, and developmental differences that are often overlooked. With the recent availability of new tools, most importantly MR1 tetramers, it is now possible to directly study MAIT cells to understand their biology. Therefore, it is timely to compare the phenotype, development, and function of MAIT cells and iNKT cells. In this review, we highlight key areas where MAIT cells show similarity or difference to iNKT cells. In addition, we discuss important avenues for future research within the MAIT cell field, especially where comparison to iNKT cells has proven less informative.

Keywords: activation; development; effector function; innate-like T cells; mucosal-associated invariant T cells; natural killer T cells; phenotype; subsets.

Figure 1

Comparison of mucosal-associated invariant T (MAIT) cell and invariant natural killer T (iNKT) cell thymic and peripheral development in mice. (A) MAIT cells and iNKT cells are positively selected by MR1- and CD1d-expressing DP (double-positive/CD4⁺CD8⁺) thymocytes, respectively. iNKT cell positive selection involves an endogenous ligand(s). A similar role for endogenous ligand(s) in MAIT cell selection is postulated, but such ligands have yet to be identified. Concomitant with T cell receptor (TCR)-MHC-Ib/ligand binding, homotypic interactions between signaling lymphocyte activation molecule (SLAM) family receptors are essential for iNKT cell, but not MAIT cell, development. (B) iNKT cells also undergo negative selection, while negative selection has not been studied for MAIT cells. (C) Following selection, MAIT and iNKT thymocytes differentiate through similar stages defined by the expression of CD24 and CD44. Stage 1 and stage 2 iNKT thymocytes are highly proliferative, whereas the proliferative capacity of thymic MAIT cells is currently unknown. A number of shared factors are required for thymic differentiation, including microRNAs (miRNAs) and PLZF, but the requirement for IL-18 and exogenous ligand (from commensal bacteria) is specific to MAIT cells. Conversely, the transcription factors Egr1, Egr2, and c-Myc have been implicated in iNKT cell development, but not investigated in MAIT cell development. iNKT cells express PLZF and exhibit effector functions at stage 1, while MAIT cells acquire effector capacity at stage 3. (D) MAIT cells and iNKT cells exit the thymus with a CD24⁻CD44⁺ memory phenotype. In the periphery, MAIT cells undergo expansion, probably driven by the presentation of exogenous ligands from commensal bacteria, whereas iNKT cell frequency remains relatively constant. (E) iNKT cell homeostasis is predominantly regulated by cytokines, in particular IL-7 and IL-15. By contrast, the role of MR1 and cytokines in MAIT cell homeostasis is currently unknown.

Figure 2

Mechanisms of mucosal-associated invariant T (MAIT) cell and invariant natural killer T (iNKT) cell activation. MAIT cells and iNKT cells are activated via three main pathways: T cell receptor (TCR)-dependent (A), TCR-independent (predominantly cytokine-driven) (B), and combined TCR-dependent and -independent (C). (A) In response to TCR signaling, MAIT cells and iNKT cells produce cytokines and exhibit cytotoxic activity. The degree of activation is modulated by costimulatory molecules, including CD161. The array of cytokines produced by iNKT cells varies upon activation of different costimulatory pathways. Whether this is also the case for MAIT cells is currently unknown. (B) TCR-independent activation is largely cytokine-mediated, with similar combinations of cytokines capable of activating both MAIT cells and iNKT cells, for example, IL-12 + IL-18. However, while IL-12 (bold) appears dominant for iNKT cell activation, IL-18 (bold) is key for MAIT cells. Cytokine-dependent activation of MAIT and iNKT cells may require prior TCR stimulation, as has been reported for human iNKT cells. As well as by cytokines, iNKT cells can be directly activated via certain natural killer (NK) cell receptors, such as NK1.1 in mice. IFN-γ production may predominate following TCR-independent activation, although this requires further investigation. (C) MAIT cells and iNKT cells can be activated through a combination of TCR and cytokine signaling. In this setting, iNKT cell antigens are typically weak self-antigens (bold), but endogenous ligands for MAIT cells have not been identified.

Figure 3

Functional capacity of mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells. Where subsets of MAIT or iNKT cells have been defined, characteristic cytokines, transcription factors, and/or surface markers, are illustrated. MAIT cells and iNKT cells exhibit overlapping functions, although a wider range of functions have been described for iNKT cells. In mice, distinct type 1 and type 17 MAIT and iNKT cell subsets have been identified. By contrast, human MAIT cells exhibit a mixed type 1/type 17 phenotype. Human iNKT cells secrete IFN-γ and IL-17 (only in vitro under pro-inflammatory conditions), but whether these cytokines are produced by distinct subsets, remains to be established. Unlike MAIT cells, iNKT cells also show type 2 functions, such as IL-4 secretion. In mice, IL-10-producing iNKT cells comprise a distinct subset with altered transcription factor expression. Human MAIT cells and iNKT cells can produce IL-10, and human IL-10-producing MAIT cells are enriched in adipose tissue, similar to mouse NKT10 cells. However, whether these IL-10-producing populations comprise distinct subsets, is currently unknown. Finally, multiple specialized subsets of iNKT cells have been identified in mice, including NKT_FH cells and iNKT_reg cells. Human iNKT cells with similar phenotypes and/or functions have also been identified (NKT_reg only in vitro), but analogous populations have yet to be described for MAIT cells.