Mucosal-associated Invariant T cells: A New Player in Innate Immunity

Yong-Wook Park; Seung-Jung Kee

doi:10.4078/jrd.2015.22.6.337

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Park and Kee: Mucosal-associated Invariant T cells: A New Player in Innate Immunity

Review Article

J Rheum Dis 2015;22(6):337-345.

Published online: 31 October 2015

DOI: https://doi.org/10.4078/jrd.2015.22.6.337

Mucosal-associated Invariant T cells: A New Player in Innate Immunity

Yong-Wook Park¹, Seung-Jung Kee²

¹Department of Rheumatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

²Department of Laboratory Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

Corresponding to: Yong-Wook Park, Department of Rheumatology, Chonnam National University Hospital, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea. E-mail: parkyw@jnu.ac.kr.

Received 14 November 2015 Accepted 22 November 2015

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that are restricted by the non-classical major histocompatibility complex class-1b molecule MR1. MAIT cells recognize riboflavin (vitamin B2) derivatives in a MR1-depen-dent manner. Following antigen recongnition, MAIT cells rapidly produce Th1/Th17 cytokines, such as interferon-γ and inter-leukin-17, in an innate-like manner. MAIT cells maintain an activated phenotype throughout the course of an infection, secrete inflammatory cytokines, and have the potential to directly kill infected cells, thus, playing an important role in controlling the host response. In this review, we discuss current knowledge regarding the role of MAIT cells in infectious diseases, cancers, and autoimmune diseases.

Keywords: Autoimmune diseases, Cytokine, MR1, Mucosal-associated invariant T cell, Vitamin B2

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Figure 1.

A schematic of key differences among conventional T cells, invariant natural killer T (iNKT) cells, and mucosal-associated invariant T (MAIT) cells in humans. In contrast to conventional adaptive T cells expressing both diverse T cell receptor (TCR) Vα and Vβ chains, MAIT cells and iNKT cells constitute two major subsets of innate-like T cells with semi-invariant TCR repertoires using TCR Vα7.2-Jα33 chains expressed together with selected TCR β chains and TCR Vα24-Jα33 chains paired with TCR Vβ11 chains, respectively. In addition, MAIT cells are characterized by a high expression of CD161 and interleukin-18Rα (IL-18Rα). MAIT cells and NKT cells recognize vitamin B2 metabolite antigens (Ag) and glycolipid Ag presented by the invariant major histocompatibility complex (MHC)-related 1 (MR1) molecule and MHC class 1-like CD1d molecule, respectively, which are both expressed on Ag-presenting cells. Upon Ag recognition, these innate-like T cells rapidly produce cytokines.

Figure 2.

Mechanisms of mucosal-associated invariant T (MAIT) cell activation in human diseases. (A) Microbial infection. Bacteria or yeast stimulate MAIT cells in an MR1-dependent manner. MAIT cells are activated through Vα7.2-bearing MAIT cell T cell receptor (TCR) recognition of microbial-derived vitamin B metabolite antigens presented by MR1 on infected antigen-presenting cells (APCs). Upon infection, MAIT cells are activated by stimulation with interleukin (IL)-12 and IL-18 produced by APCs in an MR1-independent manner. Furthermore, activation of MAIT cells can be enhanced by other stimuli, such as IL-7 secreted by hep-atocytes in synergy with TCR stimulation. Activated MAIT cells produce Th1 cytokines (interferon [IFN]-γ and tumor necrosis factor [TNF]-α) and Th17 cytokines (IL-17 and IL-22) and directly release perforin and granzyme B, which are cytotoxic effector molecules, to kill infected cells. (B) Viral infection. Viruses stimulate MAIT cells in an MR1-independent manner. Virus-infected cells are activated by detection of their molecular patterns by pattern recognition receptors, such as ssRNA by TLR8, resulting in IL-12 and IL-18 production. (C) Autoimmune disease. MAIT cells are stimulated by IL-12 and IL-18 produced by pathologically activated inflammatory cells present in autoimmune diseases. Figure adapted from an original drawing by Howson et al. (Front Immunol 2015;6:303) [2].

Table 1.

Key differences between iNKT cells and MAIT cells

Variable	iNKT cells	MAIT cells
MHC restriction	CD1d	MR1
Antigen	Glycolipids	Metabolic intermediates derived from the riboflavin biosynthetic pathway

T cell receptor	TCRV 14-J 18 (mouse) or V 24-J 18 (human) paired with limited V chains	TCRV 19-J 33 (mouse) or V 7.2-J 33/12/20 (human) paired with several V chains
Activation	CD1d-bound microbial ligands; endogenous	MR1-bound microbial ligands; endogenous MR1
	CD1d ligands; cytokines (IL-12 and IL-18)	ligands unknown; cytokines (IL-12 and IL-18)
Acquisition of effector phenotype	Exit the thymus expressing PLZF and effector memory phenotype	Exit the thymus naïve; acquire PLZF expression and effector memory phenotype in the periphery, prior to birth
Abundance	＜1% of human peripheral blood T cells (CD3＋)	1%∼10% of human peripheral blood T cells (CD3＋)
Response kinetics	Peak in numbers early, prior to conventional	Early impact on immune responses, but peak in
	CD4＋ and CD8＋ T cell responses (murine studies)	numbers concomitant with conventional CD4＋ and CD8＋ T cells (murine studies)
Microbiota influence	iNKTcell numbers increase in GF mice	MAIT cells undetectable in GF mice

GF: germfree, IL: interleukin, iNKT cell: innate natural killer T cell, MAIT: mucosal-associated invariant T cell, MHC: major histocompatibility complex, MR1: MHC class I-related protein, TCR: T cell receptor. Data was obtained from the article of Cowley (Cell Mol Life Sci 2014;71:4831-40) [11].

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