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Cutting Edge: Highly Alloreactive Dual TCR T Cells Play a Dominant Role in Graft-versus-Host Disease¹

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Alloreactivity is the response of T cells to MHC molecules not encountered during thymic development. A small population (1–8%) of peripheral T cells in mice and humans express two TCRs due to incomplete allelic exclusion of TCR, and we hypothesized they are highly alloreactive. FACS analysis of mouse T cell MLR revealed increased dual TCR T cells among alloreactive cells. Quantitative assessment of the alloreactive repertoire demonstrated a nearly 50% reduction in alloreactive T cell frequency among T cells incapable of expressing a secondary TCR. We directly demonstrated expansion of the alloreactive T cell repertoire at the single cell level by identifying a dual TCR T cell with distinct alloreactivities for each TCR. The importance of dual TCR T cells is clearly demonstrated in a parent-into-F₁ model of graft-vs-host disease, where dual TCR T cells comprised up to 60% of peripheral activated T cells, demonstrating a disproportionate contribution to disease.

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 Grant AI-061173 (to P.M.A.) and the W. M. Keck Foundation Fellowship in Molecular Medicine (to G.P.M.).

² Address correspondence and reprint requests to Dr. Paul M. Allen, Department of Pathology and Immunology, 660 South Euclid, Box 8118, St. Louis, MO 63110. E-mail address: pallen{at}wustl.edu

³ Abbreviations used in this paper: GVHD, graft-vs-host disease; BMC, bone marrow cell.

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