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CXCR4 acts as a costimulator during thymic β-selection

Nature Immunology volume 11, pages 162–170 (2010)Cite this article

Abstract

Passage through the β-selection developmental checkpoint requires productive rearrangement of segments of the T cell antigen receptor-β gene (Tcrb) and formation of a pre-TCR on the surface of CD4−CD8− thymocytes. How other receptors influence ββ-selection is less well understood. Here we define a new role for the chemokine receptor CXCR4 during T cell development. CXCR4 functionally associated with the pre-TCR and influenced β-selection by regulating the steady-state localization of immature thymocytes in thymic subregions, by facilitating optimal pre-TCR-induced survival signals, and by promoting thymocyte proliferation. We also characterize functionally relevant signaling molecules downstream of CXCR4 and the pre-TCR in thymocytes. Our data designate CXCR4 as a costimulator of the pre-TCR during β-selection.

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Figure 1: CXCR4 regulates β-selection in vivo.
Figure 2: CXCR4 deletion affects the localization and survival of early thymic progenitors in vivo.
Figure 3: CXCR4 provides differentiation and survival signals during T cell development.
Figure 4: CXCR4 is required for pre-TCR-dependent survival signals.
Figure 5: CXCR4 acts as a costimulator for the pre-TCR.
Figure 6: The pre-TCR regulates CXCR4 signaling and physically associates with CXCR4.
Figure 7: ShcA is an essential participant downstream of CXCR4 signaling for the migration and localization of DN thymocytes.

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Acknowledgements

We thank J.C. Zúñiga-Pflücker (Sunnybrook Research Institute, University of Toronto) for OP9-DL1 cells; I. Aifantis (New York University School of Medicine) for SCIET27 and SCB29 cells; the flow cytometry and histology core facilities at the University of Virginia for technical assistance; members of the Ravichandran laboratory and specifically I.J. Juncadella and M.R. Elliott for technical assistance; and J. Lysiak and R. Woodson for help with the Apostain technique. Supported by the National Institute of General Medical Sciences (K.S.R.), the National Cancer Institute (T.P.B.) and the Howard Hughes Medical Institute (D.R.L.).

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Authors and Affiliations

  1. Carter Immunology Center, University of Virginia, Charlottesville, Virginia, USA

    Paul C Trampont, Annie-Carole Tosello-Trampont, Timothy P Bender & Kodi S Ravichandran

  2. Department of Microbiology, University of Virginia, Charlottesville, Virginia, USA

    Yuelei Shen & Dan R Littman

  3. Department of Cell Biology, University of Virginia, Charlottesville, Virginia, USA

    Amanda K Duley, Timothy P Bender & Kodi S Ravichandran

  4. Howard Hughes Medical Institute, Kimmel Center for Biology and Medicine, Skirball Institute and New York University School of Medicine, New York, New York, USA

    Ann E Sutherland

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Contributions

P.C.T. designed and did the experiments and wrote the manuscript; A.-C.T.-T. did the experiments for Figures 6a,c,e,f and 7a,b and helped with the manuscript; A.K.D. provided the Rag2−/− and Rag2−/− TCRβ+ mice and provided assistance for Figure 3a; Y.S. provided the data in Figure 1b; T.B.P. and A.E.S. provided access to mouse strains and reagents; D.R.L. shared unpublished information and provided the floxed Cxcr4 mouse strain and intellectual input; and K.S.R. supervised the overall design, the conduct and interpretation of the experiments, and the writing of the manuscript.

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Correspondence to Kodi S Ravichandran.

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Trampont, P., Tosello-Trampont, AC., Shen, Y. et al. CXCR4 acts as a costimulator during thymic β-selection. Nat Immunol 11, 162–170 (2010). https://doi.org/10.1038/ni.1830

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