The overall goal of these studies is to understand how the HM genes regulate immune responses. The TIM gene family, discovered by our group in 2001 using a positional cloning strategy in congenic mice, potently regulates innate and adaptive immune responses. In the previous grant period, we showed that TIM-1 is an important costimulatory molecule for T cells and an important susceptibility gene for atopic diseases, and that TIM-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 and complementary Projects focusing on different aspects of TIM interactions with PtdSer expressed by apoptotic cells. The overall hypothesis is that the TIMs function as pattern recognition receptors that sense PtdSer as a DAMP (damage associated molecular pattern), and that the TIMs function either to clear apoptotic cells or to amplify immunity by responding to apoptotic/dying cells. In Project 1, we will study TIM-1 expressing natural killer T (NKT) cells, which function to sense and become activated by apoptotic cells in the liver and in the lungs. In Project 2, we will examine intracellular, molecular and functional consequences of PtdSer on apoptotic cells binding to TIM molecules on antigen presenting cells (APCs) and T cells. In Project 3 we will examine the role of TIMs in in vivo models of respiratory and oral tolerance, in which clearance of apoptotic cells by TIM expressing APCs plays a critical role. In Project 4 we will examine the structure of TIM proteins and the influence ofthe TIM gene polymorphisms on ligand recognition and presentation of ligand binding epitopes. Our Projects utilize unique reagents, including TIM specific mAbs, TIM-1 transgenic, TIM-4 transgenic and TIM-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 of asthma, hepatitis, respiratory tolerance and oral tolerance. Our studies will demonstrate that the T/Mgene family evolved to sense the presence of apoptotic cells at different phases of immunity, and to play a major role 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. We believe 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI054456-08
Application #
8306830
Study Section
Special Emphasis Panel (ZAI1-RRS-I (M2))
Program Officer
Minnicozzi, Michael
Project Start
2003-04-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$1,281,552
Indirect Cost
$327,939
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
Gubin, Matthew M; Zhang, Xiuli; Schuster, Heiko et al. (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577-81
Kim, Hye Young; Chang, Ya-Jen; Chuang, Ya-Ting et al. (2013) T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death. J Allergy Clin Immunol 132:414-25.e6
Albacker, L A; Yu, S; Bedoret, D et al. (2013) TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells. Mucosal Immunol 6:580-90
Jemielity, Stephanie; Wang, Jinyize J; Chan, Ying Kai et al. (2013) TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS Pathog 9:e1003232
Manangeeswaran, Mohanraj; Jacques, Jerome; Tami, Cecilia et al. (2012) Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans. Gastroenterology 142:1516-25.e3
Kim, Hye Young; Eyheramonho, Maria Belen; Pichavant, Muriel et al. (2011) A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans. J Clin Invest 121:1111-8

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