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Quantitating T Cell Cross-Reactivity for Unrelated Peptide Antigens¹

Jeffrey Ishizuka^*,, Kristie Grebe^*, Eugene Shenderov^*,, Bjoern Peters, Qiongyu Chen, YanChun Peng, Lili Wang, Tao Dong, Valerie Pasquetto, Carla Oseroff, John Sidney, Heather Hickman^*, Vincenzo Cerundolo, Alessandro Sette, Jack R. Bennink^*, Andrew McMichael and Jonathan W. Yewdell^2,*

^* Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda MD 20892; Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom; and La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

Quantitating the frequency of T cell cross-reactivity to unrelated peptides is essential to understanding T cell responses in infectious and autoimmune diseases. Here we used 15 mouse or human CD8⁺ T cell clones (11 antiviral, 4 anti-self) in conjunction with a large library of defined synthetic peptides to examine nearly 30,000 TCR-peptide MHC class I interactions for cross-reactions. We identified a single cross-reaction consisting of an anti-self TCR recognizing a poxvirus peptide at relatively low sensitivity. We failed to identify any cross-reactions between the synthetic peptides in the panel and polyclonal CD8⁺ T cells raised to viral or alloantigens. These findings provide the best estimate to date of the frequency of T cell cross-reactivity to unrelated peptides (1/30,000), explaining why cross-reactions between unrelated pathogens are infrequently encountered and providing a critical parameter for understanding the scope of self-tolerance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (to J.R.B. and J.W.Y.), by the Medical Research Council Human Immunology Unit (to T.D. and A.M.), and by Cancer Research UK (Grant C399/A2291) (to V.C.).

² Address correspondence and reprint requests to Dr. Jonathan W. Yewdell, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health Room 2E13C.1, Building 33, 33 North Drive, Bethesda, MD 20892. E-mail address: jyewdell{at}nih.gov

³ Abbreviations used in this paper: pMHC, peptide MHC complex; f_rel, frequency of T cell cross-reactivity to closely related peptides; f_un, frequency of T cell cross-reactivity to unrelated peptides; IAV, influenza A virus; ICS, intracellular cytokine staining; KO, knockout; ORF, open reading frame; SFU, spot-forming unit; Tg, transgenic; VV, vaccinia virus.

⁴ The online version of this article contains supplemental material.

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The JI 2009 183: 4143-4144. [Full Text]