Crystal structure of the MHC class Ib molecule H2-M3

Wang, C. R.; Lindahl, Kirsten Fischer; Deisenhofer, Johann

doi:10.1016/0923-2494(96)89644-1

Cited by 12 publications

(7 citation statements)

References 38 publications

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“…Thus, the greater susceptibility of MR1 to substitutions in the A versus F pockets suggests it may have a similar mechanism of terminal ligand anchoring as class Ia molecules. In addition, susceptibility to A pocket perturbations may suggest that MR1 binds ligands with a unique N terminus like the strong preference of H2-M3 for formylated peptides (66). Regardless of the explanation, the phenotype of MR1 mutants at sites involved in terminal peptide binding of class Ia molecules provides further supporting evidence that MR1 binds a ligand.…”

Section: Mr1 Mutations At Sites Involved In Terminal Peptide Binding mentioning

confidence: 79%

Evidence for MR1 Antigen Presentation to Mucosal-associated Invariant T Cells

Huang

Gilfillan

Cella

et al. 2005

Journal of Biological Chemistry

144

205

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The novel class Ib molecule MR1 is highly conserved in mammals, particularly in its ␣1/␣2 domains. Recent studies demonstrated that MR1 expression is required for development and expansion of a small population of T cells expressing an invariant T cell receptor (TCR) ␣ chain called mucosal-associated invariant T (MAIT) cells. Despite these intriguing properties it has been difficult to determine whether MR1 expression and MAIT cell recognition is ligand-dependent. To address these outstanding questions, monoclonal antibodies were produced in MR1 knock-out mice immunized with recombinant MR1 protein, and a series of MR1 mutations were generated at sites previously shown to disrupt the ability of class Ia molecules to bind peptide or TCR. Here we show that 1) MR1 molecules are detected by monoclonal antibodies in either an open or folded conformation that correlates precisely with peptide-induced conformational changes in class Ia molecules, 2) only the folded MR1 conformer activated 2/2 MAIT hybridoma cells tested, 3) the pattern of MAIT cell activation by the MR1 mutants implies the MR1/TCR orientation is strikingly similar to published major histocompatibility complex/␣␤TCR engagements, 4) all the MR1 mutations tested and found to severely reduce surface expression of folded molecules were located in the putative ligand binding groove, and 5) certain groove mutants of MR1 that are highly expressed on the cell surface disrupt MAIT cell activation. These combined data strongly support the conclusion that MR1 has an antigen presentation function.

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Section: Mr1 Mutations At Sites Involved In Terminal Peptide Binding mentioning

confidence: 79%

Evidence for MR1 Antigen Presentation to Mucosal-associated Invariant T Cells

Huang

Gilfillan

Cella

et al. 2005

Journal of Biological Chemistry

144

205

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“…Taking this into consideration, the requirements that are essential for binding to H2-M3, namely hydrophobic amino acid composition and interactions with essentially only four N-terminal residues, the number of N-terminal sequence permutations for H2-M3 ligands is limited. Of those hydrophobic peptides that do bind to H2-M3, the amino acid side chains are buried within the H2-M3-binding groove and therefore inaccessible to TCR (9,41). Hence, similar surface characteristics that are formed by the H2-M3 molecule with different ligands might result in cross-reactive recognition by a given TCR.…”

Section: Discussionmentioning

confidence: 99%

Promiscuity of MHC Class Ib-Restricted T Cell Responses

Ploß

Lauvau

Contos

et al. 2003

The Journal of Immunology

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Murine infection with the Gram-positive intracellular bacterium Listeria monocytogenes activates CD8+ T cells that recognize bacterially derived N-formyl methionine peptides in the context of H2-M3 MHC class Ib molecules. Three peptides, fMIGWII, fMIVIL, and fMIVTLF, are targets of L. monocytogenes-specific CD8+ T cells. To investigate epitope cross-recognition by H2-M3-restricted CD8+ T cells, we deleted the sequence encoding fMIGWII from a virulent strain of L. monocytogenes. Infection with fMIGWII-deficient L. monocytogenes unexpectedly primed CD8+ T cells that stain with fMIGWII/H2-M3 tetramers and lyse fMIGWII-coated target cells in vivo. Because the fMIGWII sequence is nonredundant, we speculated that other bacterially derived Ags are priming these responses. HPLC peptide fractionation of bacterial culture supernatants revealed several distinct L. monocytogenes-derived peptides that are recognized by fMIGWII-specific T cells. Our results demonstrate that the dominant H2-M3-restricted CD8+ T cell population, although reactive with fMIGWII, is primed by other, non-fMIGWII peptides derived from L. monocytogenes. Although this degree of Ag receptor promiscuity is unusual for the adaptive immune system, it may be a more common feature of T cell responses restricted by nonpolymorphic MHC class Ib molecules.

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“…Nevertheless, pathogen or tumour-derived peptides bind to numerous class Ib molecules including HLA-E, Q9, Qa-1 b , and H2-M3 (Table 1). In HFE, the antigen-binding cleft is narrowed by a shift of the a1-helix towards the a2-helix, resulting in the burial of the peptide-binding pockets so that HFE is precluded from binding peptides ( Figure 2) [21]. Nevertheless, somewhat paradoxically, T-cell responses directed at HFE have also been reported recently [22].…”

Section: Introductionmentioning

confidence: 96%