TIM-1 Glycoprotein Binds the Adhesion Receptor P-Selectin and Mediates T Cell Trafficking during Inflammation and Autoimmunity

Abstract

SUMMARY Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper-1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 IgV domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease.

Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model

“…These proteins were initially described as a hepatitis A virus receptor and a kidney injury molecule 1, which is an epithelial cell adhesion molecule upregulated during kidney ischemia (4)(5)(6). TIM proteins serve important functions in various biological activities, such as cellular proliferation, apoptosis, autophagy, migration, tissue regeneration, and immune regulation (7)(8)(9)(10)(11)(12)(13). Dysfunction of TIM proteins results in various diseases, such as rheumatic arthritis, asthma, nephritis, systemic lupus erythematosus, and intestinal allergy, most of which are autoimmune-related disorders.…”

Development of a Stable Cell Line, Overexpressing Human T-cell Immunoglobulin Mucin 1

“…Considering the role of the TIM-1 in development of autoimmune diseases and allergy, regulation of rolling of T cell subsets particularly Th1 and Th17 cell homing into the central nervous system (CNS), homeostasis of tumor microenvironment and receptor for virus entrance into host cells (2,(8)(9)(10), TIM-1 could be considered as a target for therapy of T cell-mediated diseases and virus infection using its specific monoclonal antibody, nanobody or aptamer (7,15). Iran This very high expression was obtained by pcDNA ™ 3.1/Hygro (+) vector, which contain cytomegalovirus promoter.…”

“…Moreover, TIM-1 plays critical role in Th-1 and Th-17 cell homing into the central nervous system (CNS). Thus, TIM-1 might be an important tool to achieve selective tissue homing of T cells in neurodegenerative disorders like multiple sclerosis (MS) (9). TIM-1 also regulates responses to viral infections and homeostasis of tumor microenvironment (2,10).…”

“…Therefore, interference with TIM-1 signaling, stimulating or blocking TIM-1 activity offers a novel approach for potential treatments for T cell-mediated diseases (9,16). For example, blocking TIM-1 would inhibit Th-2 proliferation and cytokine production in allergic diseases (7).…”

“…For example, blocking TIM-1 would inhibit Th-2 proliferation and cytokine production in allergic diseases (7). Also, blocking TIM-1 might be useful for preventing entry of Th1 and Th17 cells to CNS in order to help for treatment of multiple sclerosis (9).…”