A nonpolymorphic major histocompatibility complex class Ib molecule binds a large array of diverse self-peptides.

Joyce, Sebastian; Tabaczewski, Piotr; Angeletti, Ruth Hogue; Nathenson, Stanley G.; Stroynowski, Iwona

doi:10.1084/jem.179.2.579

Cited by 96 publications

(50 citation statements)

References 40 publications

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“…sA2 and sB7 were affinity purified using W6/32-bound protein A-Sepharose (GE Healthcare). Class I-associated peptide elution, separation, and reversed-phase HPLC purification were all performed as previously described (59).…”

Section: Methodsmentioning

confidence: 99%

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Gilchuk¹,

Spencer²,

Conant³

et al. 2013

J. Clin. Invest.

141

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CD8 + T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection -information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.

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Section: Methodsmentioning

confidence: 99%

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Gilchuk¹,

Spencer²,

Conant³

et al. 2013

J. Clin. Invest.

141

View full text Add to dashboard Cite

show abstract

“…Experimental results indeed have indicated that certain nonclassical class I products are involved in presentation of peptides to TCR. For example, Hint is specialized to present N-formyl peptides to TCRs (11,12) and Q7 (Qa-2) binds nonameric peptides with a particular motif (13,14). Involvement of nonclassical class I products in immune response to bacterial or stress proteins as well as in presentation of peptides to y8 TCRs was also described (reviewed in ref.…”

mentioning

confidence: 99%

Structure, function, and evolution of mouse TL genes, nonclassical class I genes of the major histocompatibility complex.

Obata

Satta

Moriwaki

et al. 1994

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

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In contrast to well-studied "classal" class I genes of the major htmpatibility complex (MHC), the biology of noncll dass I genes remains largely unexamined. The mouse TL genes constitute one of the best defined systems among class I genes In the T region of the MHC. To eucidate the function and the evolution of TL genes and their relationship to cl l class I genes, seven TL DNA sequences, including one from a Japanese wild mouse, were examined and compared with those of several mouse and human classical class I genes. The TL genes differ from either clascal class I genes or pseudogenes in the extent and pattern of nucleotide substutins. Natural selection appears to have operated so as to preserve the function of TL, which might have been acquired in an early stage of its evolution. In a putative peptide-bindngregion encoded by TL genes, the rate of nonsynonymous (amino acid replacing) substitution is considerably lower than that of synonymous substitution. This conservation is completely opposite that in classical clas I genes, in which the peptide-binding region has evolved to diveify amino acd sequences so as to recognize a variety of antigens. Thus, it is ggested that the function of TL antigens is distinct from that of c al class I antigens and is related to the recognition of a relatively restricted repertoire of antigens and their presentation to T-cell receptors.

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“…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%

“…Cells were then collected and analyzed by flow cytometry. Peptides used were PEP7 (ELLSCSHLF derived from lymphocytic choriomeningitis virus L protein) (14), L19 (ILMEHIHKL) (15), PEP2 (NQLVNLHDL derived from rabies virus glycoprotein) (14), PEP9 (TLITVRHKI derived from vaccinia virus RNA polymerase) (14), and OVA (SIINFEKL) (16). Additionally, Ala scanning was performed using peptides synthesized to contain single Ala substitutions at each position of the L19 backbone.…”

Section: Peptide-induced Mhc Stabilization Assaysmentioning

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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A nonpolymorphic major histocompatibility complex class Ib molecule binds a large array of diverse self-peptides.

Cited by 96 publications

References 40 publications

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Structure, function, and evolution of mouse TL genes, nonclassical class I genes of the major histocompatibility complex.

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

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