Systemic lupus erythematosus (SLE) is characterized by high titer IgG autoantibodies to ubiquitous intracellular components. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Autoantibodies in lupus appear to arise as a consequence of autoantigen-specific alphabeta CD4+ T cell help. Autoreactive T cells in lupus presumably bypass normal tolerance mechanisms, although mechanisms of tolerance escape for T cells responsive to ubiquitous self peptides are unknown. This proposal will address the hypothesis that lupus T cells have intrinsic (genetic) defects that render them more susceptible to activation through their T cell receptor (TCR)-CD3 complex after contact with self- peptides, a defect that contributes to tolerance loss with expansion of autoreactive, peripheral T cells. This hypothesis is based in part upon preliminary data indicating that naive, mature T cells from Fas (CD95)-intact, lupus-prone MRL (MRL/+Fas- lpr) mice are hyper-proliferative after TCR stimulation, compared to T cells from non-autoimmune mice. Indeed, the former cells are hyper-proliferative after contact with peptides having low affinity for the TCR, as determined in studies using TCR receptor transgenic MRL and control mice. To further address the hypothesis, three specific aims are planned. First, differences in in vitro activation and survival between T cells from Fas- intact MRL and non-autoimmune mice will be sought. Here, T cells from wild type and from TCR transgenic animals will be analyzed for activation, IL-2 production, death, and TCR signaling events after stimulation with anti-CD3 and with cognate and variant peptides, including those with low affinity for the transgenic TCR. Second, differences in in vivo activation and survival between MRL and control T cells will be sought via immunization or tolerance induction with cognate or variant PCC peptides. Finally, it will be determined if these differences in T cell activation phenotypes are associated with a candidate locus from the MRL genetic background. Here, activation phenotypes will be compared using T cells from non-autoimmune B6 mice and B6 mice congenic for a candidate MRL locus on chromosome 7 that may be associated with an intrinsic T cell abnormality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR040072-15
Application #
6783473
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1990-08-31
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
15
Fiscal Year
2004
Total Cost
$317,190
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie et al. (2018) Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus. JCI Insight 3:
Kim, Sang Taek; Choi, Jin-Young; Lainez, Begona et al. (2018) Human Extrafollicular CD4+ Th Cells Help Memory B Cells Produce Igs. J Immunol 201:1359-1372
Weinstein, Jason S; Laidlaw, Brian J; Lu, Yisi et al. (2018) STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med 215:337-355
Laidlaw, Brian J; Lu, Yisi; Amezquita, Robert A et al. (2017) Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci Immunol 2:
Choi, Jin-Young; Seth, Abhinav; Kashgarian, Michael et al. (2017) Disruption of Pathogenic Cellular Networks by IL-21 Blockade Leads to Disease Amelioration in Murine Lupus. J Immunol 198:2578-2588
Weinstein, Jason S; Herman, Edward I; Lainez, BegoƱa et al. (2016) TFH cells progressively differentiate to regulate the germinal center response. Nat Immunol 17:1197-1205
Ray, John P; Staron, Matthew M; Shyer, Justin A et al. (2015) The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity 43:690-702
Choi, Jin-Young; Ho, John Hsi-en; Pasoto, Sandra G et al. (2015) Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol 67:988-99
Marshall, Heather D; Ray, John P; Laidlaw, Brian J et al. (2015) The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Elife 4:e04851
Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9

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