The impact of dying cells on the immune system depends on the manner in which cells die, and the current perception is that necrotic cells act as """"""""danger"""""""" signals while apoptotic cells are """"""""silent"""""""". For adaptive immune responses, many studies have documented the immunogenic activity of necrotic cells, however it is now clear that apoptotic cells can illicit a tolerogenic response. While it is apparent that normal tissue and lymphocyte death can induce immune tolerance other studies have shown that in some cases apoptotic cells can be immunogenic. Understanding this dynamic depends on discovering the factors elicited by dying cells that mediate these effects. Our studies over the past 3 years have established a link between the molecular pathways of apoptosis and the process of immune tolerance. We have explored this in a system in which antigens associated with the remnants of cells undergoing apoptosis suppress the immune response. We now know that caspase activation, MOMP (mitochondrial outer membrane permeablization), and ROS (reactive oxygen species) production during apoptosis are important. Additionally ROS produced during apoptosis modifies the danger signal HMGB1 (for high mobility group box 1 protein) preventing its immunostimulatory effects. In this application we will further explore the effect of HMGB1 on the induction of immune tolerance by apoptotic cells. We propose 3 aims: 1) We will define the mechanism(s) by which HMGB1 blocks tolerance by apoptotic cells;2) We will determine if ROS-modified HMGB1 retains its proinflammatory functions;3) We will determine if other cell death pathways modulate the immune response by modifying danger signals through ROS production. Our finding that ROS production during apoptosis modifies the danger signal HMGB1 represents a major paradigm shift in the biology of danger signals. Thus, it is not the quantity of HMGB1 that is available, it is the quality. We would further suggest that not all ROS are harmful but may provide protection against unwanted immune responses. We believe that these new principles are wildly applicable and the studies proposed here will further define these mechanisms and determine if the potential exists to mimic those mechanisms in a therapeutic approach to modulating the immune response.
Our immune systems protect us from infection and other injuries. They can also turn against us and attack our own cells during organ transplantation and autoimmunity. The studies proposed here will improve our understanding of the immune system and lead to the development of therapies that can be use to control the immune response for our benefit.
| 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 |
| 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 |
| Ferguson, Thomas A; Green, Douglas R (2014) Autophagy and phagocytosis converge for better vision. Autophagy 10:165-7 |
| 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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