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TIM-4 Expressed on APCs Induces T Cell Expansion and Survival¹

Roselynn Rodriguez-Manzanet^2,*, Jennifer Hartt Meyers^2,3,*, Savithri Balasubramanian, Jacqueline Slavik, Nasim Kassam^*, Valerie Dardalhon^*, Edward A. Greenfield^*, Ana C. Anderson^*, Raymond A. Sobel, David A. Hafler^*, Terry B. Strom and Vijay K. Kuchroo^4,*

^* Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Biomedical Research Institute, Brigham and Women’s Hospital, Boston, Massachusetts 02115; and Laboratory Service, Veterans Affairs Health Care System, Palo Alto, California 94304, and Department of Pathology, Stanford University School of Medicine, Stanford, California 94305

TIM (T cell, Ig, mucin) proteins can regulate T cell immune responses. Tim-4 mRNA is not expressed in T cells, but exclusively in APCs. Tim-4 is a ligand for Tim-1 and Tim-4.Ig fusion protein was shown to either inhibit or expand T cells. However, the molecular basis for such opposite effects was not defined. By generating mAbs, we show that expression of Tim-4 protein is restricted to CD11c⁺ and CD11b⁺ cells and is up-regulated upon activation. We show that Tim-4 specifically phosphorylates Tim-1 and induces T cell expansion by enhancing cell division and reducing apoptosis. Tim-4 also induces the phosphorylation of signaling molecules LAT, Akt, and ERK1/2 in T cells. Tim-4, expressed on APCs, is a costimulatory molecule that promotes T cell expansion and survival by cross-linking Tim-1 on T cells.

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 research grants from the National Multiple Sclerosis Society (RG3666 and RG2571D9) and the National Institutes of Health (NS045973, NS046414, NS35685, NS30843, AI44880, AI058680, P01AI139671, P01AI41521, and P01NS38037). R. Rodriguez-Manzanet is supported by Grant F31NS056503 from the NINDS. V. K. Kuchroo is a recipient of the Javits Neuroscience Investigator Award from the National Institutes of Health.

² R.R.-M. and J.H.M. contributed equally to the work.

³ Current address: American Association of Immunologists, Bethesda, MD 20814.

⁴ Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, HIM 785, Boston, MA 02115. E-mail address: vkuchroo{at}rics.bwh.harvard.edu

⁵ Abbreviations used in this paper: TIM, T cell, Ig, mucin.