Immune responses are dependent on antigen presentation, a central event in immunity. The cells capable of performing this function in lymphoid tissues are the subject of intense study, and are increasingly found to be dendritic cells. Conversely, the cells which present antigen in non-lymphoid tissues, especially neural tissues including retina and CNS, are not well-characterized. Fundamental knowledge of the function of these cells is critical to understanding inflammation in these sensitive tissues. Our previous in vitro assays of the antigen presenting abilities of immune cells in retina found virtually no activity. In vivo, we found evidence that antigen presentation leading to retinal inflammation could be provided by cells recruited from the circulation. We also found that inoculating small numbers of isolated dendritic cells into the eye dramatically increased the strength of the pathogenic response of autoreactive T cells to a retinal antigen. As a result, we propose that the antigen presentation required to initiate CD4 T cell-mediated immune responses in retina is dependent on antigen presenting cells recruited from the circulation, rather than local cells. This hypothesis differs significantly from the current paradigm of antigen presentation in retina and CNS, which asserts that perivascular cells are the antigen presenting cells responsible for induction of CD4 T cell mediated nervous system immune responses. Consequently, basic aspects of retinal immunobiology need to be examined. The hypothesis is divided into two parts. Part A proposes that the antigen presentation required to initiate CD4 T cell-mediated experimental autoimmune uveoretinitis is dependent on antigen presenting cells recruited from the circulation, rather than on the resident microglia, or on bone marrow-derived perivascular cells that turn over slowly. Part B proposes that retinal microglia and perivascular cells play regulatory roles that attenuate retinal inflammation in this model. To address these hypotheses, autoreactive CD4 T cells specific for a retinal antigen will be inoculated into mice that either possess or lack: 1. dendritic cells; or 2. MHC class II on subsets of immune cells in the retina. The ability of circulating antigen presenting cells, or their precursors, to replace these deficiencies in antigen presentation will be tested. ? ? ? ?
| McPherson, Scott W; Heuss, Neal D; Pierson, Mark J et al. (2014) Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells. J Neuroinflammation 11:205 |
| Maldonado, Marcela; Kapphahn, Rebecca J; Terluk, Marcia R et al. (2013) Immunoproteasome deficiency modifies the alternative pathway of NF?B signaling. PLoS One 8:e56187 |
| Ferrington, Deborah A; Roehrich, Heidi; Chang, Angela A et al. (2013) Corneal wound healing is compromised by immunoproteasome deficiency. PLoS One 8:e54347 |
| McPherson, Scott W; Heuss, Neal D; Gregerson, Dale S (2013) Local ""on-demand"" generation and function of antigen-specific Foxp3+ regulatory T cells. J Immunol 190:4971-81 |
| McPherson, Scott W; Heuss, Neal D; Gregerson, Dale S (2012) Regulation of CD8(+) T Cell Responses to Retinal Antigen by Local FoxP3(+) Regulatory T Cells. Front Immunol 3:166 |
| Heuss, Neal D; Lehmann, Ute; Norbury, Christopher C et al. (2012) Local activation of dendritic cells alters the pathogenesis of autoimmune disease in the retina. J Immunol 188:1191-200 |
| McPherson, Scott W; Heuss, Neal D; Lehman, Ute et al. (2011) Generation of Regulatory T Cells to Antigen Expressed in the Retina. Curr Immunol Rev 7:344-349 |
| Lehmann, Ute; Heuss, Neal D; McPherson, Scott W et al. (2010) Dendritic cells are early responders to retinal injury. Neurobiol Dis 40:177-84 |
| Gregerson, Dale S; Heuss, Neal D; Lehmann, Ute et al. (2009) Peripheral induction of tolerance by retinal antigen expression. J Immunol 183:814-22 |
| McPherson, Scott W; Heuss, Neal D; Gregerson, Dale S (2009) Lymphopenia-induced proliferation is a potent activator for CD4+ T cell-mediated autoimmune disease in the retina. J Immunol 182:969-79 |
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