T cells of staphylococcal enterotoxin B-tolerized autoimmune MRL-lpr/lpr mice require co-stimulation through the B7-CD28/CTLA-4 pathway for activation and can be reanergized in vivo by stimulation of the T cell receptor in the absence of this co-stimulatory signal.
The CD28/CTLA-4 receptors on T cells interact with the B7 molecule on antigen-presenting cells (APC) to produce a co-stimulatory signal that determines the outcome of activation. The role of this co-stimulatory signal in T cell activation and loss of tolerance in autoimmune MRL-lpr/lpr mice has not been investigated previously. The present study examines the contribution of the CD28/CTLA-4 co-stimulatory pathway to the loss of T cell tolerance in V beta 8 transgenic MRL-lpr/lpr and (-)+/+ mice in which neonatal tolerance has been induced by the superantigen staphylococcal enterotoxin B (SEB). An artificial APC transfected with the murine B7 gene, and a CTLA-4-Ig fusion protein were used to analyze the significance of the CD28/CTLA-4 pathway in vitro. The CTLA-4-Ig fusion protein was also used to inhibit the pathway in vivo. Our results demonstrate that CD28 and CTLA-4 mRNA was overexpressed in the lymph nodes of lpr/lpr mice (MRL, C57BL/6, C3H and AKR), but not in +/+ mice of the same background strain. Lymph node T cells and thymocytes from SEB neonatally tolerized MRL-lpr/lpr mice that had undergone tolerance loss, proliferated when cultured with SEB and B7+ fibroblasts in vitro, but did not proliferate when the SEB was presented in the context of B7- fibroblasts. This in vitro tolerance loss could be prevented by blocking of B7 signaling by CTLA-4-Ig. This loss of tolerance did not occur in lymph node T cells from thymectomized MRL-lpr/lpr mice. SEB challenge of tolerized MRL-lpr/lpr mice in vivo led to weight loss, increased serum cytokine levels and depletion of V beta 8+ T cells. These effects were blocked by blocking of the co-stimulatory pathway by treatment with the CTLA-4-Ig fusion protein prior to and during challenge with SEB. T cells from thymus and lymph nodes of these mice did not proliferate later in response to stimulation in vitro with SEB even in the presence of B7+ APC. Nonresponsiveness was not due to deletion of V beta 8+ CD28+ T cells, as the number of these cells was increased after treatment with SEB and the CTLA-4-Ig fusion protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhou
T
T
Department of Medicine, University of Alabama at Birmingham.
Weaver
C
C
Linsley
P S
PS
Mountz
J D
JD
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D017635:Clonal Anergy / Q000502:physiology*; D004768:Enterotoxins / Q000276:immunology*; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D014162:Transfection; D015431:Weight Loss / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D004768:Enterotoxins; D018796:Immunoconjugates; D011948:Receptors, Antigen, T-Cell; C031818:enterotoxin B, staphylococcal; D000069594:Abatacept