1klg Citations

Minor structural changes in a mutated human melanoma antigen correspond to dramatically enhanced stimulation of a CD4+ tumor-infiltrating lymphocyte line.

J. Mol. Biol. 319 449-61 (2002)
Cited: 20 times
EuropePMC logo PMID: 12051920


While most immunotherapies for cancer have focused on eliciting specific CD8+ cytotoxic T lymphocyte killing of tumor cells, a mounting body of evidence suggests that stimulation of anti-tumor CD4+ T cell help may be required for highly effective therapy. Several MHC class II-restricted tumor antigens that specifically activate such CD4+ helper T lymphocytes have now been identified, including one from a melanoma tumor that is caused by a single base-pair mutation in the glycolytic enzyme triosephosphate isomerase. This mutation results in the conversion of a threonine residue to isoleucine within the antigenic epitope, concomitant with a greater than five log-fold increase in stimulation of a CD4+ tumor-infiltrating lymphocyte line. Here, we present the crystal structures of HLA-DR1 in complex with both wild-type and mutant TPI peptide antigens, the first structures of tumor peptide antigen/MHC class II complexes recognized by CD4+ T cells to be reported. These structures show that very minor changes in the binding surface for T cell receptor correspond to the dramatic differences in T cell stimulation. Defining the structural basis by which CD4+ T cell help is invoked in an anti-tumor immune response will likely aid the design of more effective cancer immunotherapies.

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  1. Interplay between superantigens and immunoreceptors. Petersson K, Forsberg G, Walse B. Scand. J. Immunol. 59 345-355 (2004)

Articles citing this publication (15)

  1. Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor. Deng L, Langley RJ, Brown PH, Xu G, Teng L, Wang Q, Gonzales MI, Callender GG, Nishimura MI, Topalian SL, Mariuzza RA. Nat. Immunol. 8 398-408 (2007)
  2. Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection. Calvo-Calle JM, Strug I, Nastke MD, Baker SP, Stern LJ. PLoS Pathog. 3 1511-1529 (2007)
  3. A comparative approach linking molecular dynamics of altered peptide ligands and MHC with in vivo immune responses. Knapp B, Omasits U, Schreiner W, Epstein MM. PLoS ONE 5 e11653 (2010)
  4. A polymorphic pocket at the P10 position contributes to peptide binding specificity in class II MHC proteins. Zavala-Ruiz Z, Strug I, Anderson MW, Gorski J, Stern LJ. Chem. Biol. 11 1395-1402 (2004)
  5. Structural insights into the editing of germ-line-encoded interactions between T-cell receptor and MHC class II by Vα CDR3. Deng L, Langley RJ, Wang Q, Topalian SL, Mariuzza RA. Proc. Natl. Acad. Sci. U.S.A. 109 14960-14965 (2012)
  6. Crystal structure of Mycoplasma arthritidis mitogen complexed with HLA-DR1 reveals a novel superantigen fold and a dimerized superantigen-MHC complex. Zhao Y, Li Z, Drozd SJ, Guo Y, Mourad W, Li H. Structure 12 277-288 (2004)
  7. Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. Li Y, Depontieu FR, Sidney J, Salay TM, Engelhard VH, Hunt DF, Sette A, Topalian SL, Mariuzza RA. J. Mol. Biol. 399 596-603 (2010)
  8. Protein expression of lymphocytes in HLA-DR transgenic pigs by a proteomic approach. Huang SY, Chen YH, Teng SH, Chen IC, Ho LL, Tu CF. Proteomics 6 5815-5825 (2006)
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  10. Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVβ20-1, altering pHLA recognition. Watkins S, Pichler WJ. PLoS ONE 8 e76211 (2013)
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  13. Expression and bioactivity analysis of Staphylococcal enterotoxin M and N. Pan YQ, Ding D, Li DX, Chen SQ. Protein Expr. Purif. 56 286-292 (2007)
  14. Modification of the inhibitory amino acid for epitope peptide binding onto major histocompatibility complex class II molecules enhances immunogenicity of the antigen. Chang SH, Kim J, Lee KY, Kim HJ, Chung YJ, Park CU, Kim BS, Jang YS. Scand. J. Immunol. 59 123-132 (2004)
  15. Staphylococcus enterotoxin profile of China isolates and the superantigenicity of some novel enterotoxins. Shen M, Li Y, Zhang L, Dai S, Wang J, Li Y, Zhang L, Huang J. Arch. Microbiol. 199 723-736 (2017)

Related citations provided by authors (1)

  1. Biochemical identification of a mutated human melanoma antigen recognized by CD4+ T cells. Pieper R, Christian RE, Gonzales MI, Nishimura MI, Gupta G, Settlage RE, Shabanowitz J, Rosenberg SA, Hunt DF, Topalian SL J. Exp. Med. 189 757-765 (1999)