Apoptosis plays a number of fundamental roles in the immune system. It is the process by which self reactive cells are deleted in the thymus (central deletion) and it is responsible for cell removal in the periphery (peripheral deletion). Apoptosis is important for preventing autoimmunity and ensuring the integrity of immune privileged sites. Recent studies have described the tolerogenic nature of apoptotic cells. Our proposal will explore several aspects of the apoptosis to tolerance response to determine what it is about apoptosis that leads to immune tolerance. The basis for our studies will be the well characterized tolerance system first described in 1966 by Battisto and Bloom. In this system intravenous injection of antigen-coupled splenocytes gave reproducible and potent tolerance. This method has proven effective for a wide range of haptens and antigens. Recently we demonstrated that tolerance in this system was based on apoptosis of the injected cells. Apoptosis was mediated via the Fas/FasL pathway when viable splenocytes are used however; it was apoptosis that was the key event. The studies proposed here will take a unique approach to understanding the role of apoptosis in tolerance by examining why apoptosis, and specifically apoptotic cells, are critical for normal physiology. We propose to study the following: 1) We will explore the role of FasL induced cell death in tolerance; 2) we will define what it is about the apoptotic cell, per se, that is tolerogenic; 3) we will characterize the dendritic cell (DC) responsible for tolerance by apoptotic cells; 4) we will investigate a mechanism to ablate the apoptosis to tolerance pathway and explore the consequences for the immune response. If it can be determined exactly what it is about apoptosis that is tolerogen, a better understanding of how this process helps maintain self tolerance will be gained. Consequently, these studies may lead to new strategies of intervention in important clinical problems such as graft rejection, autoimmunity and tumor biology.
| Zhou, Z; Doggett, T A; Sene, A et al. (2015) Autophagy supports survival and phototransduction protein levels in rod photoreceptors. Cell Death Differ 22:488-98 |
| Zhou, Zhenqing; Vinberg, Frans; Schottler, Frank et al. (2015) Autophagy supports color vision. Autophagy 11:1821-32 |
| Yin, Xiao-Tang; Keadle, Tammie L; Hard, Jessicah et al. (2015) Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice. J Immunol Res 2015:435140 |
| Ferguson, Thomas A; Green, Douglas R (2014) Autophagy and phagocytosis converge for better vision. Autophagy 10:165-7 |
| LeBlanc, Philippe M; Doggett, Teresa Ann; Choi, Jayoung et al. (2014) An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-induced tolerance through RAGE receptor. J Biol Chem 289:7777-86 |
| Zhao, Hui; Roychoudhury, Jayeeta; Doggett, Teresa A et al. (2013) Age-dependent changes in FasL (CD95L) modulate macrophage function in a model of age-related macular degeneration. Invest Ophthalmol Vis Sci 54:5321-31 |
| Kim, Ji-Young; Zhao, Hui; Martinez, Jennifer et al. (2013) Noncanonical autophagy promotes the visual cycle. Cell 154:365-76 |
| Mattapallil, Mary J; Wawrousek, Eric F; Chan, Chi-Chao et al. (2012) The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes. Invest Ophthalmol Vis Sci 53:2921-7 |
| Pillai, Meenu R; Collison, Lauren W; Wang, Xiaohua et al. (2011) The plasticity of regulatory T cell function. J Immunol 187:4987-97 |
| Griffith, Thomas S; Ferguson, Thomas A (2011) Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells. Immunity 35:456-66 |
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