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TIM-4 is the ligand for TIM-1, and the TIM-1–TIM-4 interaction regulates T cell proliferation

Abstract

The newly identified TIM family of proteins is associated with regulation of T helper type 1 (TH1) and TH2 immune responses. TIM-1 is genetically linked to asthma and is a receptor for hepatitis A virus, but the endogenous ligand of TIM-1 is not known. Here we show that TIM-4, which is expressed by antigen-presenting cells, is the ligand for TIM-1. In vivo administration of either soluble TIM-1–immunoglobulin (TIM-1–Ig) fusion protein or TIM-4–Ig fusion protein resulted in hyperproliferation of T cells, and TIM-4–Ig costimulated T cell proliferation mediated by CD3 and CD28 in vitro. These data suggest that the TIM-1–TIM-4 interaction is involved in regulating T cell proliferation.

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Figure 1: TIM-4 is expressed in macrophages and mature DCs, but not in T cells.
Figure 2: TIM-4 ligand is expressed on B cells and activated T cells.
Figure 3: TIM-4 specifically interacts with TIM-1.
Figure 4: The TIM-4–TIM-1 interaction in normal T cells.
Figure 5: TIM-1–Ig specifically binds activated CD11b+ and CD11c+ cells ex vivo.
Figure 6: Administration of TIM-1–Ig results in T cell hyperproliferation.
Figure 7: TIM-4–Ig induces hyperproliferation of T cells in vivo and costimulates T cell proliferation in vitro.

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Acknowledgements

Supported by the National Multiple Sclerosis Society (S.C., and grants RG-2571-D-9 and FG-1478-A-1), the National Institutes of Health (1RO1NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1RO1AI44880-03, 2P01AI39671-07, 1PO1NS38037-04 and 1F31GM20927-01; Javits Neuroscience Investigator Award, V.K.K.) and the Howard Hughes Medical Institute (J.H.M.).

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Correspondence to Vijay K Kuchroo.

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Research in the laboratory is funded in part by Telos, Inc. (San Diego, California).

Supplementary information

Supplementary Fig. 1

Tim-1-Ig administration in vivo induces hyperproliferation and enhancement of the TH2 response in a TH2-biased system. (PDF 908 kb)

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Meyers, J., Chakravarti, S., Schlesinger, D. et al. TIM-4 is the ligand for TIM-1, and the TIM-1–TIM-4 interaction regulates T cell proliferation. Nat Immunol 6, 455–464 (2005). https://doi.org/10.1038/ni1185

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