The long-term goals of Project 1 are to determine how TIM-1, which binds phsophatidylserine (PtdSer) on apoptotic cells, regulates the development of asthma. In the previous grant period, we showed that TIMl is an important atopy susceptibility gene interacting with the envirormient, and that TIM-1 is an important receptor for PtdSer. In the next grant period, we will extend these observations, and hypothesize that asthma is regulated by Natural Killer T (NKT) cells expressing TIM-1, and activated by apoptotic bronchial epithelial cells expressing PtdSer. We will show that NKT cells activated by apoptotic cells in the airways can amplify innate and adaptive immunity, and cause airway hyperreactivity (AHR), a cardinal feature of asthma.
In Specific Aim 1, we propose to clarify the mechanisms by which TIM-1 costimulates the activation of NKT cells. We will demonstrate that apoptotic cells bind to and activate NKT cells, in a TIM-1 and PtdSer specific manner. Moreover, we will show that such a pathway can occur in vivo, by establishing an in vivo model in which liver cells, made apoptotic by treatment with anti-Fas mAb, activate NKT cells, which are present in large numbers in the liver.
In Specific Aim 2, we hypothesize that the hepatitis A virus (HAV), by binding to TIM-1 on human NKT cells, can activate the NKT cells. We will show that that HAV-activated NKT cells are cytotoxic for hepatocytes, and suggest that these HAV-activated NKT cells later protect against the development of asthma. We will also show that TIMl, a susceptibility gene for asthma, is also a susceptibility gene for severe HAV infection and hepatitis. Moreover, by examining a monkey model of HAV infection, we will demonstrate that HAV infection is indeed associated with the activation and expansion of hepatic NKT cells.
In Specific Aim 3, we will examine how NKT cells, responding through TIM-1 to apoptotic airway epithelial cells in the lung, mediate AHR. We hypothesize that oxidative stress in the airways causes airway epithelial cell apoptosis, which can then activate NKT cells, resulting in the development of AHR. Our studies will be facilitated by unique reagents, including primary NKT cell lines, activating and blocking anti-TIM-1 mAb, TIM-1 Tg mice, TIM -/- mice, TIM-3-/- mice, Nrf2 -/- mice and Rhesus monkeys. These studies will provide significant insight into an important human atopy susceptibility gene (TIMl). Moreover, we will demonstrate that TIM-1 on NKT cells functions as a pattern recognition receptor that senses PtdSer as a DAMP (damage associated molecular pattern), and that apoptotic bronchial epithelial cells provide a 'danger' signal that activates NKT cells, profoundly affecting airway inflammation and asthma.
Asthma and allergy (atopic diseases) affect up to 40% of the general population; and are major public health problems with limited therapies. We propose study how TIMl; which we identified as an important atopy susceptibility gene; affects the development of asthma. We believe that our studies will uncover very important novel concepts of how inflammation develops in the lungs; and may lead to a better understanding of how the environment affects asthma and to curative therapies for asthma and allergy.
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|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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