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TCR Chain That Forms Peptide-Independent Alloreactive TCR Transfers Reduced Reactivity with Irrelevant Peptide/MHC Complex¹

Fabio R. Santori^2,3,*, Zoran Popmihajlov^2,4,*, Vladimir P. Badovinac, Courtney Smith, Sasa Radoja, John T. Harty and Stanislav Vukmanovi^5,*,

^* Michael Heidelberger Division of Immunology, Department of Pathology and New York University Cancer Center, New York University School of Medicine, New York, NY 10016; Department of Microbiology, University of Iowa, Iowa City, IA 52242; and Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC 20010

A major feature of the TCR repertoire is strong alloreactivity. Peptides presented by allogeneic MHC are irrelevant for recognition by a subset of alloreactive T cells. To characterize peptide-independent TCRs at the molecular level, we forced the expression of a TCR chain isolated from a peptide-independent alloreactive CD8⁺ T cell line. The alloreactive TCR repertoire in the transgenic mouse was peptide dependent. However, analysis of essential TCR contacts formed during the recognition of self-MHC-restricted Ag showed that fewer contacts with peptide were established by the transgenic TCR chain, and that this was compensated by additional contacts formed by endogenous TCR chains. Thus, reduced interaction with the peptide appears to be a transferable feature of the peptide-independent TCR chain. In addition, these findings demonstrate that reactivity to peptides is preferred over the reactivity to MHC during the formation of the TCR repertoire.

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 National Institutes of Health Grants AI48837 and AI41573 (to S.V.) and AI42767 (to J.T.H.).

² F.R.S. and Z.P. contributed equally to this work and should both be considered first authors.

³ Current address: Skirball Institute for Molecular Medicine, Department of Pathology and New York University Cancer Center, New York University School of Medicine, 540 First Avenue, New York, NY 10016.

⁴ Current address: Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, 515 East 71st Street, S-222, New York, NY 10021.

⁵ Address correspondence and reprint requests to Dr. Stanislav Vukmanovi, Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010. E-mail address: svukmano{at}cnmc.org

⁶ Abbreviations used in this paper: ₂m, ₂ microglobulin; WT, wild type; LM, Listeria monocytogenes.

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