Ocular immune privilege enables the eye to respond to antigenic challenges in ways that preserve the delicate structures of the eye. Although we and others have found active and passive mechanisms of immune privilege to retinal antigens, the details are not yet clear. Passive mechanisms produce immunological ignorance, the functional absence of interactions between the immune system and retinal antigens. In part, immunological ignorance is due to sequestration resulting from the blood/retinal barrier, which reduces lymphocytic perusal of the retina, minimizes leakage of antigens, and limits conventional lymphatic drainage. Based on our recent results, we propose that the lack of local antigen presenting cells is an important complementary mechanism of immunological ignorance closely associated with sequestration. Since it is clear that activated T cells access the retinal Parenchyma in spite of the barriers, limiting the antigen presenting cells would further constrain potential encounters with antigen, thus reducing potential inflammation and damage. In this respect, ? it appears that the retina differs from other CNS tissue, which is well-endowed with antigen presenting cells. Previous studies concentrated on CD4 T cells, their MHC class II-restricted responses, and the pathogenesis of CD4 T cell mediated responses to retinal antigens. The antigen presenting cells that were the focus of those studies were the microglia and perivascular cells - retinal cells capable of expressing MHC class II. In contrast, Aim I of this proposal examines the mechanism of the near-surgical, precision killing of retinal neurons, long thought to be MHC class I-negative, by CD8 T cells. This observation raises fundamental questions regarding the mechanisms by which class I-restricted T cells eliminate cells that appear to be class I negative, and express the target antigen intracellularly. Curiously, antigen-negative, MHC class I-negative neurons in the cerebellum (granule cells) are also killed. Our approach is based on mice with transgenic expression of the target antigen beta-galactosidase in either neurons (photoreceptor cells) or microglia (astrocytes, MHC class I-positive), enabling this critical distinction to be tested.
Aim II examines the possibility that local antigen presenting cells are limiting, in number and/or function, thus contributing to retinal immune ignorance and privilege. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011542-11
Application #
7104939
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
1996-08-01
Project End
2010-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
11
Fiscal Year
2006
Total Cost
$364,967
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Schuld, Nathan J; Hussong, Stacy A; Kapphahn, Rebecca J et al. (2015) Immunoproteasome deficiency protects in the retina after optic nerve crush. PLoS One 10:e0126768
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
Ferrington, Deborah A; Gregerson, Dale S (2012) Immunoproteasomes: structure, function, and antigen presentation. Prog Mol Biol Transl Sci 109:75-112
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
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
Gregerson, Dale S; Heuss, Neal D; Lehmann, Ute et al. (2009) Peripheral induction of tolerance by retinal antigen expression. J Immunol 183:814-22
Gregerson, Dale S; Heuss, Neal D; Lehmann, Ute et al. (2008) Evidence for extrathymic generation of regulatory T cells specific for a retinal antigen. Ophthalmic Res 40:154-9
Ferrington, Deborah A; Hussong, Stacy A; Roehrich, Heidi et al. (2008) Immunoproteasome responds to injury in the retina and brain. J Neurochem 106:158-69

Showing the most recent 10 out of 24 publications