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Tim-1 Signaling Substitutes for Conventional Signal 1 and Requires Costimulation to Induce T Cell Proliferation¹

Christophe Mariat^2,*, Nicolas Degauque^2,*, Savithri Balasubramanian^*, James Kenny^*, Rosemarie H. DeKruyff, Dale T. Umetsu, Vijay Kuchroo, Xin Xiao Zheng^* and Terry B. Strom^3,*

^* Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Division of Immunology, Children’s Hospital, and Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Differentiation and clonal expansion of Ag-activated naive T cells play a pivotal role in the adaptive immune response. T cell Ig mucin (Tim) proteins influence the activation and differentiation of T cells. Tim-3 and Tim-2 clearly regulate Th1 and Th2 responses, respectively, but the precise influence of Tim-1 on T cell activation remains to be determined. We now show that Tim-1 stimulation in vivo and in vitro induces polyclonal activation of T cells despite absence of a conventional TCR-dependent signal 1. In this model, Tim-1-induced proliferation is dependent on strong signal 2 costimulation provided by mature dendritic cells. Ligation of Tim-1 upon CD4⁺ T cells with an agonist anti-Tim-1 mAb elicits a rise in free cytosolic calcium, calcineurin-dependent nuclear translocation of NF-AT, and transcription of IL-2. Because Tim-4, the Tim-1 ligand, is expressed by mature dendritic cells, we propose that interaction between Tim-1⁺ T cells and Tim-4⁺ dendritic cells might ensure optimal stimulation of T cells, when TCR-derived signals originating within an inflamed environment are weak or waning.

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 the Société de Néphrologie (to C.M.), the Société Francophone de Transplantation (to C.M.), the National Institute of Allergy and Infectious Disease (to X.X.Z., D.T.U., and T.B.S.), and the Juvenile Diabetes Research Foundation Center for Immunologic Tolerance at Harvard (to T.B.S.).

² C.M. and N.D. contributed equally to this work and should be considered as co-first authors.

³ Address correspondence and reprint requests to Dr. Terry B. Strom, Transplant Institute, Beth Israel Deaconess Medical Center, 330 Brookline Avenue-E/CLS Room 608, Boston, MA 02215. E-mail address: tstrom{at}bidmc.harvard.edu

⁴ Abbreviations used in this paper: Tim, T cell Ig mucin; BM-DC, bone marrow-derived dendritic cell; DC, dendritic cell; fluo-3-AM, fluo-3-acetoxymethyl ester; KO, knockout.