3l6f Citations

Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells.

Abstract

Dysregulated protein phosphorylation is a hallmark of malignant transformation. Transformation can generate major histocompatibility complex (MHC)-bound phosphopeptides that are differentially displayed on tumor cells for specific recognition by T cells. To understand how phosphorylation alters the antigenic identity of self-peptides and how MHC class II molecules present phosphopeptides for CD4(+) T-cell recognition, we determined the crystal structure of a phosphopeptide derived from melanoma antigen recognized by T cells-1 (pMART-1), selectively expressed by human melanomas, in complex with HLA-DR1. The structure revealed that the phosphate moiety attached to the serine residue at position P5 of pMART-1 is available for direct interactions with T-cell receptor (TCR) and that the peptide N-terminus adopts an unusual conformation orienting it toward TCR. This structure, combined with measurements of peptide affinity for HLA-DR1 and of peptide-MHC recognition by pMART-1-specific T cells, suggests that TCR recognition is focused on the N-terminal portion of pMART-1. This recognition mode appears to be distinct from that of foreign antigen complexes but is remarkably reminiscent of the way autoreactive TCRs engage self- or altered self-peptides, consistent with the tolerogenic nature of tumor-host immune interactions.

Articles - 3l6f mentioned but not cited (2)

  1. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, International Inflammatory Bowel Disease Genetics Consortium, Australia and New Zealand IBDGC, Belgium IBD Genetics Consortium, Italian Group for IBD Genetic Consortium, NIDDK Inflammatory Bowel Disease Genetics Consortium, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, Quebec IBD Genetics Consortium, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. Nat. Genet. 47 172-179 (2015)
  2. An effective and effecient peptide binding prediction approach for a broad set of HLA-DR molecules based on ordered weighted averaging of binding pocket profiles. Shen WJ, Zhang S, Wong HS. Proteome Sci 11 S15 (2013)


Reviews citing this publication (8)

  1. The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Slingluff CL. Cancer J 17 343-350 (2011)
  2. The clinical implications of antitumor immunity in head and neck cancer. Allen CT, Judd NP, Bui JD, Uppaluri R. Laryngoscope 122 144-157 (2012)
  3. Chimeric antigen receptors in cancer immuno-gene therapy: current status and future directions. Chicaybam L, Sodré AL, Bonamino M. Int. Rev. Immunol. 30 294-311 (2011)
  4. Building proteomic tool boxes to monitor MHC class I and class II peptides. Schumacher FR, Delamarre L, Jhunjhunwala S, Modrusan Z, Phung QT, Elias JE, Lill JR. Proteomics 17 (2017)
  5. Building proteomic tool boxes to monitor MHC class I and class II peptides. Schumacher FR, Delamarre L, Jhunjhunwala S, Modrusan Z, Phung QT, Elias JE, Lill JR. Proteomics 17 (2017)
  6. The clinical implications of antitumor immunity in head and neck cancer. Allen CT, Judd NP, Bui JD, Uppaluri R. Laryngoscope 122 144-157 (2012)
  7. The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination? Slingluff CL. Cancer J 17 343-350 (2011)
  8. Chimeric antigen receptors in cancer immuno-gene therapy: current status and future directions. Chicaybam L, Sodré AL, Bonamino M. Int. Rev. Immunol. 30 294-311 (2011)

Articles citing this publication (9)

  1. Genetic basis for clinical response to CTLA-4 blockade in melanoma. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA. N. Engl. J. Med. 371 2189-2199 (2014)
  2. Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids. Gauba V, Grünewald J, Gorney V, Deaton LM, Kang M, Bursulaya B, Ou W, Lerner RA, Schmedt C, Geierstanger BH, Schultz PG, Ramirez-Montagut T. Proc. Natl. Acad. Sci. U.S.A. 108 12821-12826 (2011)
  3. Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex. Wang XX, Li Y, Yin Y, Mo M, Wang Q, Gao W, Wang L, Mariuzza RA. Proc. Natl. Acad. Sci. U.S.A. 108 15960-15965 (2011)
  4. Re-Directing CD4(+) T Cell Responses with the Flanking Residues of MHC Class II-Bound Peptides: The Core is Not Enough. Holland CJ, Cole DK, Godkin A. Front Immunol 4 172 (2013)
  5. Structure-based design of altered MHC class II-restricted peptide ligands with heterogeneous immunogenicity. Chen S, Li Y, Depontieu FR, McMiller TL, English AM, Shabanowitz J, Kos F, Sidney J, Sette A, Rosenberg SA, Hunt DF, Mariuzza RA, Topalian SL. J. Immunol. 191 5097-5106 (2013)
  6. Induction of tumor-reactive T helper responses by a posttranslational modified epitope from tumor protein p53. Kumai T, Ishibashi K, Oikawa K, Matsuda Y, Aoki N, Kimura S, Hayashi S, Kitada M, Harabuchi Y, Celis E, Kobayashi H. Cancer Immunol. Immunother. 63 469-478 (2014)
  7. Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation. Capello M, Caorsi C, Bogantes Hernandez PJ, Dametto E, Bertinetto FE, Magistroni P, Rendine S, Amoroso A, Novelli F. Immunol. Lett. 167 11-16 (2015)
  8. Chemically modified peptides based on the membrane-proximal external region of the HIV-1 envelope induce high-titer, epitope-specific nonneutralizing antibodies in rabbits. Venditto VJ, Wieczorek L, Molnar S, Teque F, Landucci G, Watson DS, Forthal D, Polonis VR, Levy JA, Szoka FC. Clin. Vaccine Immunol. 21 1086-1093 (2014)
  9. Resurrecting ancestral structural dynamics of an antiviral immune receptor: adaptive binding pocket reorganization repeatedly shifts RNA preference. Pugh C, Kolaczkowski O, Manny A, Korithoski B, Kolaczkowski B. BMC Evol. Biol. 16 241 (2016)