Biochemical Features of the MHC-Related Protein 1 Consistent with an Immunological Function

Miley, Michael J.; Truscott, Steven M.; Yu, Yanbo; Gilfillan, Susan; Fremont, Daved H.; Hansen, Ted H.; Lybarger, Lonnie

doi:10.4049/jimmunol.170.12.6090

Cited by 91 publications

(117 citation statements)

References 66 publications

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“…In contrast to NKT cells, MAIT cells appear in the periphery following bacterial colonization 14 , suggesting that commensal bacteria-derived signals and/or antigens are important in sustaining their expansion and survival. MAIT cells recognize small microbial metabolites produced in the riboflavin pathway 15 , when presented as stimulatory complexes with the non-polymorphic major histocompatibility complex (MHC) class I-like related molecule 1 (MR1) [16][17][18] . Whether riboflavin-related metabolites are the only antigens stimulating MAIT cells, and how these antigens affect MAIT cell expansion and homeostasis remains to be elucidated.…”

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confidence: 99%

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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confidence: 99%

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

et al. 2014

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“…Chase was initiated by the addition of an excess of unlabeled Cys/Met (5 mM each). Immunoprecipitation and endoglycosidase H (Endo H; ICN Pharmaceuticals, Costa Mesa, CA) treatment were performed as described (32). Samples were subjected to SDS-PAGE, and gels were treated with Amplify (Amersham Biosciences), dried, and exposed to BioMax-MR film (Eastman Kodak Co.).…”

Section: Methodsmentioning

confidence: 99%

The Viral E3 Ubiquitin Ligase mK3 Uses the Derlin/p97 Endoplasmic Reticulum-associated Degradation Pathway to Mediate Down-regulation of Major Histocompatibility Complex Class I Proteins

Wang

Lencer³

et al. 2006

Journal of Biological Chemistry

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Ubiquitin E3 ligases are important cellular components for endoplasmic reticulum (ER)-associated degradation due to their role in substrate-specific ubiquitination, which is required for retrotranslocation (dislocation) of most unwanted proteins from the ER to the cytosol for proteasome degradation. However, our understanding of the molecular mechanisms of how E3 ligases confer substratespecific recognition, and their role in substrate retrotranslocation is limited especially in mammalian cells. mK3 is a type III ER membrane protein encoded by murine ␥ herpesvirus 68. As conferred by its N-terminal RING-CH domain, mK3 has E3 ubiquitin ligase activity. In its role as an immune evasion protein, mK3 specifically targets nascent major histocompatibility complex class I heavy chains (HC) for rapid degradation. The mechanism by which mK3 extracts HC from the ER membrane into the cytosol for proteasome-mediated degradation is unknown. Evidence is presented here that HC down-regulation by mK3 is dependent on the p97 AAA-ATPase. By contrast, the kK5 protein of Kaposi's sarcomaassociated herpesvirus is p97-independent despite the fact that it is highly homologous to mK3. mK3 protein was also found in physical association with Derlin1, an ER protein recently implicated in the retrotranslocation of HC by immune evasion protein US11, but not US2, of human cytomegalovirus. The mechanistic implications of these findings are discussed.To exist in the presence of an active host immune system, herpesviruses in particular have elaborate mechanisms of immune evasion. For example, to specifically block CD8 T cell detection of infected cells, murine ␥ herpesvirus 68 (␥HV68) expresses the mK3 protein. The mK3 protein is a viral RING-CH type ubiquitin E3 ligase (1) that specifically ubiquitinates MHC 2 class I heavy chains (HC) causing their rapid degradation in a proteasome dependent manner (2, 3). Thus mK3 inhibits surface class I expression and its antigen presentation function required for cytolytic T cell detection of virus infected cells. Consistent with these findings, the lack of mK3 expression by the virus results in the detection of more virus-immune CD8 T cells and a lower level of latency (4).Comparisons of coding sequences revealed that mK3 is highly homologous to both kK3 and kK5 gene products of Kaposi's sarcomaassociated herpesvirus (KSHV) (1, 5). The kK3, kK5, and mK3 proteins share a common topology including a highly conserved, N-terminal RING-CH domain, followed by two predicted transmembrane segments and a C-terminal domain varying in sequence and length (3, 6, 7). Immunofluorescence studies confirmed that these K3 homologs are type III membrane proteins with both N-and C termini on the cytosolic face of the ER membrane (3, 6). The RING-CH domain possesses ubiquitin E3 ligase activity as demonstrated by its ability to carry out autoubiquitination in vitro and substrate ubiquitionation in cells (3,7,8). Additional K3 homologs are also found in poxviruses, such as M153R from myxoma virus (9). Cellular K3 homologs hav...

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“…Other significant features are the remarkable abundance of MAIT cells, which comprise approximately 5% of T cells in peripheral blood11, 17 and 20–40% of liver T cells in humans,15, 21 and their wide tissue distribution in blood, mucosal tissues, liver and joints 15, 19, 22, 23, 24, 25. A peculiarity of MAIT cell biology is that although MR1 expression is ubiquitous,3, 26 it is normally found only at very low levels on the cell surface 26, 27, 28. This has led to speculation that if other classes of MAIT cell ligand exist, they might include autologous molecules whose presentation at the cell surface occurs only when MR1 surface expression is up‐regulated as a signal of cell stress,2, 27, 29 as occurs with other class 1b molecules 14, 30.…”

Section: Introductionmentioning

confidence: 99%

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

2016

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SummaryMucosal‐associated invariant T (MAIT) cells are a novel class of innate‐like T cells, expressing a semi‐invariant T‐cell receptor (TCR) and able to recognize small molecules presented on the non‐polymorphic MHC‐related protein 1. Their intrinsic effector‐memory phenotype, enabling secretion of pro‐inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune‐mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation‐induced down‐regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR‐independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers.

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Biochemical Features of the MHC-Related Protein 1 Consistent with an Immunological Function

Cited by 91 publications

References 66 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 Viral E3 Ubiquitin Ligase mK3 Uses the Derlin/p97 Endoplasmic Reticulum-associated Degradation Pathway to Mediate Down-regulation of Major Histocompatibility Complex Class I Proteins

Mucosal‐associated invariant T cells in autoimmunity, immune‐mediated diseases and airways disease

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