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Multiple Constraints at the Level of TCR Rearrangement Impact V14i NKT Cell Development¹

Elizabeth Hager^2,*, Abbas Hawwari, Jennifer L. Matsuda^*, Michael S. Krangel and Laurent Gapin^3,*

^* Integrated Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Science Center, Denver, CO 80206; and Department of Immunology, Duke University Medical Center, Durham, NC 27710

CD1d-restricted NKT cells that express an invariant V14 TCR represent a subset of T cells implicated in the regulation of several immune responses, including autoimmunity, infectious disease, and cancer. Proper rearrangement of V14 with the J18 gene segment in immature thymocytes is a prerequisite to the production of a TCR that can be subsequently positively selected by CD1d/self-ligand complexes in the thymus and gives rise to the NKT cell population. We show here that V14 to J rearrangements are temporally regulated during ontogeny providing a molecular explanation to their late appearance in the thymus. Using mice deficient for the transcription factor ROR and the germline promoters T early- and J49, we show that developmental constraints on both V and J usage impact NKT cell development. Finally, we demonstrate that rearrangements using V14 and J18 occur normally in the absence of FynT, arguing that the effect of FynT on NKT cell development occurs subsequent to -chain rearrangement. Altogether, this study provides evidence that there is no directed rearrangement of V14 to J18 segments and supports the instructive selection model for NKT cell selection.

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 J.L.M. is a recipient of an American Cancer Society Award. This work was supported by grants from the Cancer League of Colorado (to L.G.) and the National Institutes of Health (AI057485 (to L.G.) and GM41052 (to M.S.K.)).

² Current address: Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213.

³ Address correspondence and reprint requests to Dr. Laurent Gapin, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: gapinl{at}njc.org

⁴ Abbreviations used in this paper: DP, double positive; GalCer, -galactosylceramide; ROR, retinoic acid receptor-related orphan receptor; TEA, T early ; WT, wild type; CDR, complementary determining region.