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Suppression of murine SLE by oral anti-CD3: inducible CD4+CD25-LAP+ regulatory T cells control the expansion of IL-17+ follicular helper T cells

Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts, USA

EM Center

Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts, USA

GC Tsokos

Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts, USA

HL Weiner

Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts, USA, hweiner{at}rics.bwh.harvard.edu

Lupus is an antibody-mediated autoimmune disease. The production of pathogenic, class switched and affinity maturated autoantibodies in lupus is dependent on T cell help. A potential mechanism of disease pathogenesis is a lack of control of pathogenic T helper cells by regulatory T cells in lupus. It has been repeatedly shown that the naturally occurring CD4+CD25+ regulatory T cells in lupus prone mice and patients with SLE are defective both in frequency and function. Thus, the generation of inducible regulatory T cells that can control T cell help for autoantibody production is a potential avenue for the treatment of SLE. We have found that oral administration of anti-CD3 monoclonal antibody attenuated lupus development and arrested on-going disease in lupus prone SNF1 mice. Oral anti-CD3 induces a CD4+CD25-LAP+ regulatory T cell that secrets high levels of TGF-β and suppresses in vitro in TFG-β-dependent fashion. Animals treated with oral anti-CD3 had less glomerulonephritis and diminished levels of anti-dsDNA autoantibodies. Oral anti-CD3 led to a downregulation of IL-17+CD4+ICOS-CXCR5+ follicular helper T cells, CD138+ plasma cells and CD73+ mature memory B cells. Our results show that oral anti-CD3 induces CD4+CD25-LAP+ regulatory T cells that suppress lupus in mice and is associated with downregulation of T cell help for autoantibody production.

Key Words: CD4+CD25-LAP+ regulatory T cells • IL-17+ follicular helper T cells • oral anti-CD3 • spontaneous lupus

Lupus, Vol. 18, No. 7, 586-596 (2009)
DOI: 10.1177/0961203308100511


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