The goal of Project 2 is to understand how TIM proteins regulate immune responses and autoimmunity via their recognition of phosphatidylserine on apoptotic cells. We discovered the Tim (T cell- Imunoglobulin-Mucin) genes, which we showed regulate tolerance, Th2 cytokine production, and asthma. We propose to:
Specific Aim 1. Determine the functional consequences of TIM-4 and TIM-3 on APC binding to phosphatidylserine on apoptotic cells. We will examine effects on (a) anti-inflammatory cytokine production: IL-10, TGF-|3;(b) expression of coinhibitory molecules: PD-L1, PD-L2, B7-H3, B7-H4;(c) expression of co-stimulatory molecules: B7-1, B7-2, ICOS-L, CD40;(d) PGE2 and IDO production.
Specific Aim 2. Determine the functional consequences of TIM-4 and TIM-3 on APC binding to phosphatidylserine in a pro-inflammatory context and determine the effects of TIM-1 and TIM-3 on T cells binding to PtdSer on an apoptotic APC. We will examine the (a) effects of TIM-4 or TIM-3 mediated phagocytosis of apoptotic versus necrotic cells on APC function in pro-inflammatory conditions;(b) determine the effects on T cell activation and TReg development of TIM-1 and TIM-3 on T cells binding to PtdSer on an apoptotic APC;and (c) determine how the health of the APC regulates T cell responses through TIM-1 and TIM-3.
Specific Aim 3. Determine the structure/function relationship of TIM alleles on recognition of phosphatidylserine, phagocytosis, and T cell activation. We will perform a mutational analysis of the TIM-4 phosphatidylserine binding site and functional consequences of these mutations on phagocytosis;determine if HBA and BALB/c alleles of TIM-1 and TIM-3 have different capacities to recognize PtdSer and phagocytose apoptotic cells;and (c) determine how TIM-1 costimulation affects T cell activation in vitro and compare responses of TIM-1-expressing T cells from HBA and BALB/c mice. These studies together will greatly increase our understanding of the function of TIMs in the regulation of tolerance and Th2 responses, and will characterize a crucial regulator of CD4 T cell differentiation and a novel and extremely important asthma susceptibility gene family.

Public Health Relevance

TIM proteins recognize dead cells and help remove them from the body. We will find out how the TIMs remove dead cells and how this regulates the immune response. This will allow us to understand the development of and design therapies for asthma, allergies, and autoimmune disease.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Dana-Farber Cancer Institute
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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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