Discovering naturally processed antigenic determinants that confer protective T cell immunity
Pavlo Gilchuk, Charles T. Spencer, Stephanie B. Conant, Timothy Hill, Jennifer J. Gray, Xinnan Niu, Mu Zheng, John J. Erickson, Kelli L. Boyd, K. Jill McAfee, Carla Oseroff, Sine R. Hadrup, Jack R. Bennink, William Hildebrand, Kathryn M. Edwards, James E. Crowe Jr., John V. Williams, Søren Buus, Alessandro Sette, Ton N.M. Schumacher, Andrew J. Link, Sebastian Joyce
Pavlo Gilchuk, Charles T. Spencer, Stephanie B. Conant, Timothy Hill, Jennifer J. Gray, Xinnan Niu, Mu Zheng, John J. Erickson, Kelli L. Boyd, K. Jill McAfee, Carla Oseroff, Sine R. Hadrup, Jack R. Bennink, William Hildebrand, Kathryn M. Edwards, James E. Crowe Jr., John V. Williams, Søren Buus, Alessandro Sette, Ton N.M. Schumacher, Andrew J. Link, Sebastian Joyce
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Technical Advance Immunology

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Abstract

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.

Authors

Pavlo Gilchuk, Charles T. Spencer, Stephanie B. Conant, Timothy Hill, Jennifer J. Gray, Xinnan Niu, Mu Zheng, John J. Erickson, Kelli L. Boyd, K. Jill McAfee, Carla Oseroff, Sine R. Hadrup, Jack R. Bennink, William Hildebrand, Kathryn M. Edwards, James E. Crowe Jr., John V. Williams, Søren Buus, Alessandro Sette, Ton N.M. Schumacher, Andrew J. Link, Sebastian Joyce

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Figure 5

The majority of TCD8 generated against naturally processed determinants confer protective immunity to VACV.

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The majority of TCD8 generated against naturally processed determinants ...
(A) Two vaccination schemes. Scheme I entailed priming with peptide formulated with anti-CD40 antibody and poly(I:C), while scheme II entailed priming with epitope-pulsed maturated DCs. (B–E) The top row of panels correspond to peptide vaccination using scheme I; the bottom row of panels correspond to vaccination using scheme II. (B) Epitope-specific TCD8 frequency determined with the indicated p/B7.2 tetramers in blood of vaccinated mice before VACV challenge. nd, not detected. (C) Lung VACV burdens in lethally infected mice evaluated on day 6 p.i. (D) Percentage of initial body weight for epitope-vaccinated mice weighed on day 6 after challenge. The dotted line indicates no recovery threshold (i.e., ~70% initial body weight). (E) Morbidity score for epitope-vaccinated mice evaluated on day 6 after challenge. Data are representative of 2 independent experiments. Each symbol represents 1 mouse (n = 5 per epitope). Horizontal bars indicate the mean. ***P < 0.001; **P < 0.01; *P < 0.05; ns, not significant as compared with mock in 1-way ANOVA with Dunnett’s post-hoc test. Mean ± SEM in D and E are shown.