Promiscuous Antigen Presentation by the Nonclassical MHC Ib Qa-2 Is Enabled by a Shallow, Hydrophobic Groove and Self-Stabilized Peptide Conformation

Xiao, He; Tabaczewski, Piotr; Ho, Joseph; Stroynowski, Iwona; García, K. Christopher

doi:10.1016/s0969-2126(01)00689-x

Cited by 50 publications

(44 citation statements)

References 53 publications

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“…The GPI-anchored Qa-2 molecule, implicated in innate and adaptive responses, specifically appears to be a resistance gene for murine cysticercosis (38). Qa-2 can still associate with a substantially more diverse array of peptides than other nonclassical MHC class Ib molecules, but due to special constraints in the hydrophobic binding groove, the number of ligands is more limited compared with MHC class Ia molecules (39).…”

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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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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“…Three peptides were recognized and two of these contained HLA-A*0201 binding motifs (Ag85A [48][49][50][51][52][53][54][55][56] and Ag85A 242-250 ). Using CD8 + T cells purified from the peripheral blood of BCG-vaccinated individuals, specific tetramers and an IFNγ Elispot was used to determine the frequency of Ag85A-specific T cells (see Table I).…”

Section: Respectively)mentioning

confidence: 99%

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

2006

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There are more cases of tuberculosis in the world today than at anytime in history. The global epidemic has generated intense interest into the immunological mechanisms that control infection. While CD4 + T cells play a critical role in host immunity to Mycobacterium tuberculosis, there is considerable interest in understanding the role of other T cell subsets in preventing disease development following infection. CD8 + T cells are required for optimum host defense following M. tuberculosis infection, which has led to investigation of how this protective effect is mediated. A critical review of recent literature regarding the role of CD8 + T cells in protective immunity to M. tuberculosis infection is now required to address the strengths and weaknesses of these studies. In this review, we evaluate the evidence that CD8 + T cells are critical in immunity to M. tuberculosis infection. We discuss the specific mycobacterial proteins that are recognized by CD8 + T cells elicited during infection. Finally, we examine the effector mechanisms of CD8 + T cells generated during infection and synthesize recent studies to consider the protective roles that these T cells serve in vivo.

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“…At this point it is unclear whether the tumor-expressed Qa-2 ligand is a nonameric peptide with unusual structural properties or perhaps another compound that has high affinity for the Qa-2 groove. The crystal structure of Q9 bound to one of the most abundant self-peptides associating with this class I molecule, L19, showed an unusual mode of interaction (26). The endogenous peptide makes few specific contacts and exhibits extremely poor shape complementarity to the MHC groove, raising a possibility that this ligand occupies the groove by default and may be easily displaced.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies showed that Q9 has a unique peptide-binding motif among all class I Ags (14,15,25) and binds unusual peptides that form internal, intrapeptide contacts (26). The two dominant anchors include His residue at position 7 and a hydrophobic amino acid (Leu, Ile, or Phe) at position 9.…”

Section: Q8 Binds Peptides With the Q9 Peptide-binding Motifmentioning

confidence: 99%

The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

Chiang

Stroynowski

2006

The Journal of Immunology

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The mouse multimember family of Qa-2 oligomorphic class I MHC genes is continuously undergoing duplications and deletions that alter the number of the two “prototype” Qa-2 sequences, Q8 and Q9. The frequent recombination events within the Q region lead to strain-specific modulation of the cumulative Qa-2 expression levels. Q9 protects C57BL/6 hosts from multiple disparate tumors and functions as a major CTL restriction element for shared tumor-associated Ags. We have now analyzed functional and structural properties of Q8, a class I MHC that differs significantly from Q9 in the peptide-binding, CTL-interacting α1 and α2 regions. Unexpectedly, we find that the extracellular domains of Q8 and Q9 act similarly during primary and secondary rejection of tumors, are recognized by cross-reactive antitumor CTL, have overlapping peptide-binding motifs, and are both assembled via the transporter associated with the Ag processing pathway. These findings suggest that shared Ag-presenting functions of the “odd” and “even” Qa-2 loci may contribute to the selective pressures shaping the haplotype-dependent quantitative variation of Qa-2 protein expression.

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Promiscuous Antigen Presentation by the Nonclassical MHC Ib Qa-2 Is Enabled by a Shallow, Hydrophobic Groove and Self-Stabilized Peptide Conformation

Cited by 50 publications

References 53 publications

Promiscuity of MHC Class Ib-Restricted T Cell Responses

Promiscuity of MHC Class Ib-Restricted T Cell Responses

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

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