Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites

Sakala, Isaac G.; Kjer‐Nielsen, Lars; Eickhoff, Christopher S.; Wang, Xiaoli; Blazevic, Azra; Liu, Ligong; Fairlie, David P.; Rossjohn, Jamie; McCluskey, James; Fremont, Daved H.; Hansen, Ted H.; Hoft, Daniel F.

doi:10.4049/jimmunol.1402545

Cited by 118 publications

(147 citation statements)

References 83 publications

(140 reference statements)

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“…ϩ Ag-presenting cells (40). This raises the possibility that the variability of MAIT TCR ␤-chain and J␣ usage might also be driven by avoidance of self-reactivity to polymorphic MHC-I and MHC-II molecules by the relatively fixed MAIT TCR.…”

Section: Mr1mentioning

confidence: 99%

Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells

Eckle

Corbett

Keller

et al. 2015

Journal of Biological Chemistry

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117

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Vitamin B2 (riboflavin) is essential for metabolic functions and is synthesized by many bacteria, yeast, and plants, but not by mammals and other animals, which must acquire it from the diet. In mammals, modified pyrimidine intermediates from the microbial biosynthesis of riboflavin are recognized as signature biomarkers of microbial infection. This recognition occurs by specialized lymphocytes known as mucosal associated invariant T (MAIT) cells. The major histocompatibility class I-like antigen-presenting molecule, MR1, captures these pyrimidine intermediates, but only after their condensation with small molecules derived from glycolysis and other metabolic pathways to form short-lived antigens. The resulting MR1-Ag complexes are recognized by MAIT cell antigen receptors (␣␤ T cell receptors (TCRs)), and the subsequent MAIT cell immune responses are thought to protect the host from pathogens at mucosal surfaces. Here, we review our understanding of how these novel antigens are generated and discuss their interactions with MR1 and MAIT TCRs. MAIT CellsT cells are lymphocytes that mediate a range of immune functions such as killing infected host cells and producing cytokines and other factors that regulate immunity and inflammation. T cells generally recognize peptide antigens (Ags) 6 or lipid-based Ags complexed to specialized Ag-presenting molecules, MHC and CD1, respectively, that interact with an Agspecific ␣␤ T cell receptor (TCR) (1, 2). An expansive repertoire of TCRs is generated by the random rearrangement of V, D, and J gene segments and by pairing of TCR ␣-and ␤-chains, allowing specific recognition of a diverse range of Ags. Mucosal associated invariant T (MAIT) cells are a specialized subset of ␣␤ T cells originally identified in CD4 Ϫ CD8 Ϫ (double negative) human blood lymphocytes expressing a dominant invariant TCR ␣-chain gene rearrangement, TRAV1-2-TRAJ33 (based on IMGT, or V␣7.2-J␣33 based on Arden nomenclature (3)) (4, 5) with less frequent usage of TRAJ12 and TRAJ20 (6 -9). The MAIT TCR ␣-chain contains a complementarity-determining region (CDR) 3 loop of constant length with two variable amino acids in the V-J junction (4) located at the base of this loop (10, 11). MAIT cells are evolutionarily conserved in mammals with the canonical TCR ␣-chain composed of homologous TRAV and TRAJ elements also found in mice, cattle (5) and sheep (12). TRAV1-2 is not exclusive to MAIT cells, with some MHC-Irestricted T cells (13,14) and CD1b-restricted germline-encoded, mycolyl lipid-reactive (GEM) T cells also using this TRAV gene segment (15).The ␤-chain of MAIT cells has no apparent restrictions in J␤ usage, but there is a bias toward the use of human TRBV20 and TRBV6 segments (or V␤2 and V␤13 based on Arden nomenclature) and, similarly in mice, to TRBV19 and TRBV13 (or V␤6 and V␤8 based on Arden nomenclature), both being the murine orthologous segments of human TRBV6 (4, 5, 9). Furthermore, recent TCR sequencing revealed a marked oligoclonality of MAIT TCR CDR3␤ regions and a bias in the length of most...

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Section: Mr1mentioning

confidence: 99%

Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells

Eckle

Corbett

Keller

et al. 2015

Journal of Biological Chemistry

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117

132

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“…The recent development of epitope-loaded human and mouse MR1 tetramers has enabled the accurate identification of antigen-specific MAIT cells directly ex vivo (6,12,30,31). We took advantage of the fact that MR1 is highly conserved in mammals (32) to quantify and characterize a distinct population of tetramer-reactive MAIT cells in the peripheral blood and tissues of RMs.…”

Section: Identification Of Mait Cells In Rhesus Macaque Peripheral Blmentioning

confidence: 99%

Mucosa-Associated Invariant T Cells Are Systemically Depleted in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Vinton

Rossjohn

et al. 2016

J Virol

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Mucosa-associated invariant T (MAIT) cells contribute to host immune protection againstM ucosa-associated invariant T (MAIT) cells are relatively abundant in humans, comprising 1 to 10% of peripheral blood T cells (1-3) and up to 45% of liver lymphocytes (4, 5). Lower frequencies are present in the gastrointestinal (GI) tract, lung, and mesenteric lymph nodes (MLNs) (2, 6). Classically defined by the expression of a semi-invariant TRAV1-2/TRAJ33 (V␣7.2/J␣33) T cell receptor alpha (TCR␣) chain (7), MAIT cells recognize microbial vitamin B 2 metabolites presented in association with the major histocompatibility complex class I-related molecule MR1 (8-12). These conserved features bestow widespread reactivity against an array of bacterial and fungal species (13, 14), allowing MAIT cells to act as innate-like antimicrobial guardians at mucosal sites via the secretion of proinflammatory and tissue-protective cytokines, such as interleukin 17 (IL-17), tumor necrosis factor (TNF), and gamma interferon (IFN-␥) (2, 9).The abundance of MAIT cells in peripheral blood and mucosal tissues, combined with their broad reactivity and functional properties, suggests a key role in primary immune defense and various pathological states (2, 9). Indeed, multiple reports have described a loss of circulating MAIT cells in diseases with an inflammatory component, such as obesity and type II diabetes (15), inflammatory bowel disease (16), tuberculosis (2, 17), and human immunodeficiency virus (HIV) disease (18)(19)(20). MAIT cells also appear to be highly activated under these conditions and may be recruited to tissue sites of inflammation (15,16,19).Although MAIT cells are neither directly activated nor directly infected by HIV (20), previous studies have consistently demonstrated selective depletion of this subset in the peripheral blood of HIV-infected individuals and simian immunodeficiency virus (SIV)-infected Asian macaques (18)(19)(20). However, the underlying mechanisms remain unclear. It is established that CD4 ϩ T cells are lost in the GI tract during HIV/SIV infection (21,22). Moreover, epithelial integrity is compromised by the associated immunopathology, leading to microbial translocation and systemic immune activation (23,24). This process could feasibly drive MAIT cell

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“…Most of these Vβ6 + or Vβ8 + T cells are activated by bacteria (6,38). These TCR-α Tg models allow the study of MAIT specificity and antibacterial activity in vitro and in vivo (6,39,40), even if, in contrast to humans, most MAITs display a naive CD44 lo phenotype (32). This is probably related to the forced premature expression of the TCR-α chain transgene, which also greatly modifies the functionality of the Tg T cells (41).…”

Section: Introductionmentioning

confidence: 99%

Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

Cui¹,

Franciszkiewicz²,

Mburu³

et al. 2015

Journal of Clinical Investigation

148

165

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International audienceMucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-α chain and restricting molecule MR1, this population is rare in laboratory mouse strains (≈0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-α locus and led to higher usage of the distal Vα segments, including Vα19. We generated a MAIThi congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44+) CD4-CD8lo/neg T cells with tissue-homing properties (CCR6+CCR7-). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18Rα, and IL-12Rβ and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptor γ (RORγt). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIThi congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease

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Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal-Associated Invariant T Cells Specific for Riboflavin Metabolites

Cited by 118 publications

References 83 publications

Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells

Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells

Mucosa-Associated Invariant T Cells Are Systemically Depleted in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

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