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Uneven Colonization of the Lymphoid Periphery by T Cells That Undergo Early TCR Rearrangements¹

Department of Immunology, University of Washington, Seattle, WA 98195

A sparse population of thymocytes undergoes TCR gene rearrangement early in development, before the double-positive stage. The potential of these cells to contribute to the peripheral T cell pool is unknown. To examine the peripheral T cell compartment expressing a repertoire biased to early TCR gene rearrangements, we developed a mouse model in which TCR rearrangements are restricted to the double-negative stage of thymocyte development. These mice carry floxed RAG2 alleles and a Cre transgene driven by the CD4 promoter. As expected, conventional T cell development is compromised in such Cre⁺ RAG2^fl/fl mice, and the TCRβ⁺ T cells that develop are limited in their TCR repertoire, preferentially using early rearranging V genes. In the gut, the Thy-1⁺TCRβ⁺ intraepithelial lymphocyte (IEL) compartment is surprisingly intact, whereas the Thy-1^–TCRβ⁺ subset is almost completely absent. Thus, T cells expressing a TCR repertoire that is the product of early gene rearrangements can preferentially populate distinct IEL compartments. Despite this capacity, Cre⁺ RAG2^fl/fl T cell progenitors cannot compete with wild-type T cell progenitors in mixed bone marrow chimeras, suggesting that in normal mice, there is only a small contribution to the peripheral T cell pool by cells that have undergone early TCR rearrangements. In the absence of wild-type competitors, aggressive homeostatic proliferation in the IEL compartment can promote a relatively normal Thy-1⁺ TCRβ⁺ T cell pool from the limited population derived from Cre⁺ RAG2^fl/fl progenitors.

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 AG13078 and AI064318 (to P.J.F.) and National Cancer Institute Basic and Cancer Immunology Grant (to D.W.H.).

² Address correspondence and reprint requests to Dr. Pamela J. Fink, Department of Immunology, University of Washington, Box 357650, Seattle, WA 98195. E-mail address: pfink{at}u.washington.edu

³ Abbreviations used in this paper: DN, double negative; AF750, AlexaFluor 750; DP, double positive; HPRT, hypoxanthine guanine phosphoribosyltransferase; IEL, intraepithelial lymphocyte; LN, lymph node; MLN, mesenteric LN; PP, Peyer’s patch; SP, single positive; TL, thymic leukemia; TP, triple positive; WT, wild type; IMGT, ImMunoGeneTics database.