RNA-binding nuclear antigens are a major class of autoantigen targeted in systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjvgren's syndrome (SS). The mechanisms that normally mediate immunologic tolerance to RNA-binding nuclear antigens and the specific tolerance pathways that are breached in the setting of systemic autoimmunity are not well understood, although it is known that T helper (Th) cells are crucial for disease in murine lupus models. We have developed the first and only mouse transgenic for an RNA-binding nuclear antigen-specific TCR T cell receptor (TCR) in order to delineate specific mechanisms leading to T cell tolerance. By transferring T cells specific for the clinically relevant human La/SS- B antigen (hLa) into mice transgenic for physiologic expression of hLa and tracking their numbers, phenotype and function, we will delineate the mechanisms leading to peripheral T cell tolerance (Aim 1). Preliminary studies have shown that the mode of tolerance adopted by these T cells depends on the level of antigen presentation in the recipients and that the in vivo cues promoting Foxp3+ regulatory T cells in this system differ from those previously described. Analysis of antigen presenting cell (APC) and T cell phenotypes in mice mildly (2X) over-expressing RNA-binding Toll-like receptor 7 (TLR7) in the absence of other lupus susceptibility loci suggest that one cue could be constitutive stimulation of nucleic acid-binding TLR. This hypothesis and its mechanism will be investigated in Aim 1. Mice that over-express TLR7 2X in the absence of other lupus susceptibility loci are healthy and harbor tolerant T cells, whereas mice that over-express TLR7 >4X above normal develop severe, fatal lupus that is T cell dependent. The precise peripheral tolerance mechanisms that are abrogated in CD4+ anti-hLa specific T cells following their transfer into hLa transgenic mice that express TLR7 >4X and their subsequent differentiation into distinct Th and T effector cell phenotypes will be evaluated in Aim 2. We will also determine whether these fates associate with the loss of particular tolerance mechanisms such as deletion and Foxp3+ Treg conversion, and determine the roles of IL-6 and IL-21 in promoting pathogenic Th cell differentiation in this model. Very few studies exist that have investigated the role of in vivo DC in promoting CD4+ T cell tolerance in the steady state, and no such studies for nucleic acid- binding nuclear antigens have been described.
In Aim 3, we will determine whether B cells, conventional dendritic cells (DC) or plasmacytoid DC, are essential for promoting the peripheral tolerance of CD4+ T cells specific for this representative RNA-binding nuclear antigen by following the numbers, phenotype and function of anti-hLa-specific T cells in hLa transgenic mice that have been selectively depleted of these cell types. Conversely, we will determine the relative importance of B cells and DC in promoting loss of tolerance and differentiation of anti-hLa specific T cells into pathogenic Th and T effector cell types in the setting of pathogenic (>4X) TLR7 expression. These studies will define the mechanisms of CD4+ T cell tolerance and its loss for a major class of antigen that is targeted in systemic autoimmune disease.

Public Health Relevance

Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are chronic, debilitating autoimmune diseases that affect the immune system. The immune systems of humans and mice have natural mechanisms designed to maintain self-tolerance and respond to infection and inflammation. We seek to understand how these elements control CD4+ T cell fate and phenotype under both steady-state and inflammatory conditions so that we can better understand the development of autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048097-09
Application #
8277356
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2009-05-22
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$282,398
Indirect Cost
$109,148
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Pan, Z-J; Horton, C G; Lawrence, C et al. (2016) Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B. Clin Exp Immunol 186:18-29
Yaciuk, Jane C; Pan, Yujun; Schwarz, Karen et al. (2015) Defective selection of thymic regulatory T cells accompanies autoimmunity and pulmonary infiltrates in Tcra-deficient mice double transgenic for human La/Sjögren's syndrome-B and human La-specific TCR. J Immunol 194:1514-22
Edgar, Contessa E; Terrell, Deirdra R; Vesely, Sara K et al. (2015) Ribosomal and immune transcripts associate with relapse in acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura. PLoS One 10:e0117614
Maier-Moore, Jacen S; Horton, Christopher G; Mathews, Shirley A et al. (2014) Interleukin-6 deficiency corrects nephritis, lymphocyte abnormalities, and secondary Sjögren's syndrome features in lupus-prone Sle1.Yaa mice. Arthritis Rheumatol 66:2521-31
Andrews, Sarah F; Zhang, Qingzhao; Lim, Samuel et al. (2013) Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity. J Exp Med 210:125-42
Horton, Christopher G; Farris, A Darise (2012) Toll-like receptors in systemic lupus erythematosus: potential targets for therapeutic intervention. Curr Allergy Asthma Rep 12:1-7
Charles, Elizabeth; Joshi, Sunil; Ash, John D et al. (2010) CD4 T-cell suppression by cells from Toxoplasma gondii-infected retinas is mediated by surface protein PD-L1. Infect Immun 78:3484-92
Pan, Zi-jian; Maier, Shannon; Schwarz, Karen et al. (2010) Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells. Ann Rheum Dis 69:1195-9
Horton, Christopher G; Pan, Zi-jian; Farris, A Darise (2010) Targeting Toll-like receptors for treatment of SLE. Mediators Inflamm 2010:
Dudek, Nadine L; Maier, Shannon; Chen, Zhen-Jun et al. (2007) T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the HLA class II haplotype DRB1*0301/DQB1*0201. Arthritis Rheum 56:3387-98

Showing the most recent 10 out of 20 publications