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.
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.
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| Costafreda, Maria Isabel; Kaplan, Gerardo (2018) HAVCR1 (CD365) and Its Mouse Ortholog Are Functional Hepatitis A Virus (HAV) Cellular Receptors That Mediate HAV Infection. J Virol 92: |
| Chuang, Ya-Ting; Leung, Krystle; Chang, Ya-Jen et al. (2018) A natural killer T-cell subset that protects against airway hyperreactivity. J Allergy Clin Immunol : |
| Kamphorst, Alice O; Wieland, Andreas; Nasti, Tahseen et al. (2017) Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423-1427 |
| Santiago, César; Mudgal, Gaurav; Reguera, Juan et al. (2017) Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection. Sci Rep 7:46045 |
| Morales-Kastresana, Aizea; Telford, Bill; Musich, Thomas A et al. (2017) Labeling Extracellular Vesicles for Nanoscale Flow Cytometry. Sci Rep 7:1878 |
| 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 |
| 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 |
| 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 |
| Baumeister, Susanne H; Freeman, Gordon J; Dranoff, Glenn et al. (2016) Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol 34:539-73 |
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