The overall goal of these studies is to understand how the HM genes regulate immune responses. The TIMgene family, discovered by our group in 2001 using a positional cloning strategy in congenic mice, potentlyregulates innate and adaptive immune responses. In the previous grant period, we showed that TIM-1 is animportant costimulatory molecule for T cells and an important susceptibility gene for atopic diseases, and thatTIM-4 and TIM-1 function as receptors for phosphatidylserine (PtdSer). a critical marker of apoptotic cells. The current Program Project builds on these seminal findings, and consists of four interconnected andcomplementary Projects focusing on different aspects of TIM interactions with PtdSer expressed by apoptoticcells. The overall hypothesis is that the TIMs function as pattern recognition receptors that sense PtdSer as aDAMP (damage associated molecular pattern), and that the TIMs function either to clear apoptotic cells or toamplify immunity by responding to apoptotic/dying cells. In Project 1, we will study TIM-1 expressingnatural killer T (NKT) cells, which function to sense and become activated by apoptotic cells in the liver andin the lungs. In Project 2, we will examine intracellular, molecular and functional consequences of PtdSer onapoptotic cells binding to TIM molecules on antigen presenting cells (APCs) and T cells. In Project 3 wewill examine the role of TIMs in in vivo models of respiratory and oral tolerance, in which clearance ofapoptotic cells by TIM expressing APCs plays a critical role. In Project 4 we will examine the structure ofTIM proteins and the influence ofthe TIM gene polymorphisms on ligand recognition and presentation ofligand binding epitopes. Our Projects utilize unique reagents, including TIM specific mAbs, TIM-1 transgenic, TIM-4 transgenic andTIM-I''' and TIM-3''' mice, TIM crystals, monkeys and complementary approaches involving crystallogra phy, structural biology, virology, biochemistry as well as cellular and molecular immunology, in models ofasthma, hepatitis, respiratory tolerance and oral tolerance. Our studies will demonstrate that the T/Mgenefamily evolved to sense the presence of apoptotic cells at different phases of immunity, and to play a majorrole in regulating distinct compartments of mucosal immune responses by affecting cell activation, survival,death and immune tolerance. The results of these studies will greatly impact our understanding of immunity,and may lead to important new therapies for inflammatorv diseases, including asthma and food allergy.

Public Health Relevance

The 7//W genes have been shown to be important disease susceptibility genes (asthma, allergy,atopic dermatitis, food allergy and rheumatoid arthritis) and to potently regulate immune responses. Webelieve that further study of these molecules will greatly improve our understanding of disease mechanisms,and are likely to lead to novel therapies for asthma and food allergy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-RRS-I (M2))
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Minnicozzi, Michael
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Dana-Farber Cancer Institute
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Foks, Amanda C; Engelbertsen, Daniel; Kuperwaser, Felicia et al. (2016) Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice. Arterioscler Thromb Vasc Biol 36:456-65
Kim, Hye Young; Umetsu, Dale T; Dekruyff, Rosemarie H (2016) Innate lymphoid cells in asthma: Will they take your breath away? Eur J Immunol 46:795-806
Brauner, Eran; Gunda, Viswanath; Vanden Borre, Pierre et al. (2016) Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. Oncotarget 7:17194-211
Mahoney, Kathleen M; Rennert, Paul D; Freeman, Gordon J (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561-84
Mahoney, Kathleen M; Freeman, Gordon J; McDermott, David F (2015) The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther 37:764-82
Echbarthi, Meriem; Zonca, Manuela; Mellwig, Rachel et al. (2015) Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse. Traffic 16:1193-207
Kroy, Daniela C; Ciuffreda, Donatella; Cooperrider, Jennifer H et al. (2014) Liver environment and HCV replication affect human T-cell phenotype and expression of inhibitory receptors. Gastroenterology 146:550-61
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Recacha, Rosario; Jiménez, David; Tian, Li et al. (2014) Crystal structures of an ICAM-5 ectodomain fragment show electrostatic-based homophilic adhesions. Acta Crystallogr D Biol Crystallogr 70:1934-43
Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara et al. (2014) TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity. Immunity 40:542-53

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