Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor

Reantragoon, Rangsima; Patel, Onisha; Chen, Zhenjun; Illing, Patricia T.; Bhati, Mugdha; Kostenko, Lyudmila; Bharadwaj, Mandvi; Meehan, Bronwyn S.; Hansen, Ted H.; Godfrey, Dale I.; Rossjohn, Jamie; McCluskey, James

doi:10.1084/jem.20112095

Cited by 168 publications

(239 citation statements)

References 64 publications

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“…We did not find amino acid motifs within the CDR3b, although it does contact the MR1-a1 chain 31,32 . The absence of conserved motifs is consistent with the known absence of effects on antigen reactivity on single amino acid substitutions in the CDR3b chain of MAIT TCR 30,46 . We instead found that MAIT cells displayed a bias in the length of the CD3b domain, with the vast majority of the clonotypes …”

Section: Discussionsupporting

confidence: 83%

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Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

et al. 2014

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Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize conserved bacterial antigens derived from riboflavin precursors, presented by the nonpolymorphic MHC class I-like molecule MR1. Here we show that human MAIT cells are remarkably oligoclonal in both the blood and liver, display high inter-individual homology and exhibit a restricted length CDR3b domain of the TCRVb chain. We extend this analysis to a second sub-population of MAIT cells expressing a semi-invariant TCR conserved between individuals. Similar to 'conventional' MAIT cells, these lymphocytes react to riboflavin-synthesizing microbes in an MR1-restricted manner and infiltrate solid tissues. Both MAIT cell types release Th0, Th1 and Th2 cytokines, and sCD40L in response to bacterial infection, show cytotoxic capacity against infected cells and promote killing of intracellular bacteria, thus suggesting important protective and immunoregulatory functions of these lymphocytes.

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Section: Discussionsupporting

confidence: 83%

“…A recent study suggested that the TCRb chain might be less important for MAIT cell stimulation than was previously thought 30 . To investigate whether the TCRVb chains of MAIT cells have unique features, we compared the CDR3b length in MAIT and non-MAIT cells at amino acid level.…”

Section: Cdr3b Length Distribution Differs In Mait and Non-mait Cellsmentioning

confidence: 92%

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

et al. 2014

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“…Furthermore, microbial-independent cross-species reactivity between mouse and human MAIT cells and their MR1 orthologs (3) has been previously observed. Position 151 on the MR1 α2 helix was implicated in cross-species reactivity (16), and was further shown to enhance human MAIT cell reactivity when mutated to an alanine (18). Taken together, these observations suggest that MAIT cell reactivity to MR1 appears to be a balance between MR1 availability on the cell-surface, which may be modulated by endogenous, small-molecule ligands that can support MR1 expression and stability, and other features that can enhance TCR binding, such as species-specific differences in the α-helices, in particular at position 151, or the presence of stimulatory smallmolecule ligands from exogenous sources.…”

mentioning

confidence: 99%

The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins

López‐Sagaseta¹,

Dulberger²,

Crooks

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

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Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, crossspecies reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/ MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands.M ucosal-associated invariant T (MAIT) cells are a highly conserved T-cell subset found in most mammalian species (1-4). In humans, they can constitute up to 10% of circulating double-negative T cells, although they are much less frequent in mice (1,5,6). Most MAIT cells lack expression of the CD4 or CD8 coreceptors, although many MAIT cells express the αα form of the CD8 coreceptor (1). In humans, these cells are found at moderate frequency in the intestine and represent up to ∼50% of T cells in the liver (7). The cells exhibit an effector-memory phenotype and express the CD161 receptor (6). Their presence as mature effector cells in the periphery is dependent on B cells and the gut commensal flora (6, 8). Stimulated human MAIT cells can express both proinflammatory cytokines (IFN-γ, TNF-α, and IL-17) and cytolytic effectors (granzyme B) (7, 9, 10). MAIT cells are known best for their reactivity against various microorganisms from both bacterial and fungal origin (9, 10). These microorganisms include several important human pathogens, such as Mycobacterium tuberculosis, Salmonella typhimurium, and Staphylococcus aureus. Indeed, a significant proportion of the nonclassically restricted responding T cells in M. tuberculosisinfected individuals were determined to be of the MAIT lineage (9). MAIT cells have also demonstrated autoreactivity and have been associated with various autoimmune disorders (11, 12); they have also been found in both k...

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Section: Discussionmentioning

confidence: 99%

“…MR1 encodes an antigen-presenting molecule specialized in presenting microbial vitamin B6 metabolites (41,42). The protein is also involved in the development and expansion of a small population of T-cells expressing an invariant T-cell receptor alpha chain called mucosal-associated invariant T-cells (42,43). Mucosal-associated invariant T-cells lymphocytes are preferentially located in the gut lamina propria and therefore may be involved in monitoring commensal flora or serve as a distress signal (44,45).…”

Section: Discussionmentioning

confidence: 99%

751 Identification of a Common Variant With Potential Pleiotropic Effect on Risk of Inflammatory Bowel Disease and Colorectal Cancer

Khalili¹,

Brenner²,

Austin³

et al. 2013

Gastroenterology

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Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11 794 CRC cases and 14 190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E−05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

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Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor

Abstract: Crystal structure and mutagenesis analyses suggest a MAIT TCR–MR1 docking mode distinct from the NKT TCR-CD1d docking mode.

Cited by 168 publications

References 64 publications

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins

751 Identification of a Common Variant With Potential Pleiotropic Effect on Risk of Inflammatory Bowel Disease and Colorectal Cancer

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