James Crowe
Faculty Member
Last active: 3/31/2019

Discovering naturally processed antigenic determinants that confer protective T cell immunity.

Gilchuk P, Spencer CT, Conant SB, Hill T, Gray JJ, Niu X, Zheng M, Erickson JJ, Boyd KL, McAfee KJ, Oseroff C, Hadrup SR, Bennink JR, Hildebrand W, Edwards KM, Crowe JE, Williams JV, Buus S, Sette A, Schumacher TN, Link AJ, Joyce S
J Clin Invest. 2013 123 (5): 1976-87

PMID: 23543059 · PMCID: PMC3635741 · DOI:10.1172/JCI67388

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.

MeSH Terms (17)

Animals Antigen Presentation Antigens CD8-Positive T-Lymphocytes Epitopes Epitopes, T-Lymphocyte HeLa Cells Histocompatibility Antigens Class I Humans Immunodominant Epitopes Mass Spectrometry Mice Mice, Transgenic Peptides Phenotype T-Lymphocytes Vaccinia virus

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