Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate destruction of insulin-producing cells in the pancreas. Consequently, research in T1D has been heavily focused on the biology of auto-reactive T cells. However, numerous studies have pointed to defects in antigen- presenting cells (APC) in individuals with T1D. We have recently discovered that Tim-4, one of the molecules expressed on dendritic cells (DCs), plays a critical role in the development of T1D. Tim-4 has relatively restricted expression in that it is largely expressed on activated DCs and some subsets of CD11b+ macrophages in tissue inflammation. In addition, our observations suggest that Tim-4 is required for cross-presentation by CD8+ DCs. Our preliminary data demonstrates that blocking Tim-4 in vivo by the administration of anti-Tim-4 antibody results in reversal of T1D in early onset diabetes in the NOD mice. Tim-4 is has been shown to be a phosphotidylserine receptor and has a critical role in clearing apoptotic bodies in certain tissue niches, but we have observed that TIM-4 also costimulates and expands effector T cells and disarms Foxp3+ regulatory T cells. Based on the preliminary data we hypothesize that Tim-4 blockade regulates development of T1D at multiple levels by different mechanisms, including blockade of cross-presentation, inhibiting trafficking of antigen loaded DCs and regulating the balance between the diabetogenic effector and regulatory T cells. To address this hypothesis, we propose the following specific aims: 1. To identify the mechanism by which Tim-4 regulates development of immune and autoimmune responses. 2. To determine the effectiveness and mechanism by which Tim-4 blockade prevents and even reverses (new onset) diabetes in the NOD model. With a panel of novel reagents including antibodies, TIM-4 fusion protein and TIM-4-/- mice, we are proposing a multifaceted, interdisciplinary approach consisting of functional, genetic, and molecular approaches to identify mechanisms by which Tim-4 expressed on APCs regulates the development of a diabetogenic T cell response and reverses development of T1D. As our preliminary studies point to a striking effect of anti-TIM-4 antibody treatment on reversing the development of T1D, our anticipated findings are likely to have direct translational relevance to type 1 diabetes in humans.

Public Health Relevance

This project is of direct relevance to type 1 diabetes, as we are studying the mechanism by which Tim-4 blockade in vivo reverses the development of type 1 diabetes and improves islet graft acceptance in an autoimmune setting. Our data has direct translational relevance for treating patients with type 1 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Spain, Lisa M
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Brigham and Women's Hospital
United States
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Thornley, Thomas B; Agarwal, Krishna A; Kyriazis, Periklis et al. (2016) Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes. PLoS One 11:e0150792
Anderson, Ana C; Sullivan, Jenna M; Tan, Dewar J et al. (2015) A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation. J Autoimmun 59:38-42
Ji, Haofeng; Liu, Yuanxing; Zhang, Yu et al. (2014) T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury. Hepatology 60:2052-2064
Czuczman, Mark A; Fattouh, Ramzi; van Rijn, Jorik M et al. (2014) Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread. Nature 509:230-4
Thornley, Thomas B; Fang, Zemin; Balasubramanian, Savithri et al. (2014) Fragile TIM-4-expressing tissue resident macrophages are migratory and immunoregulatory. J Clin Invest 124:3443-54