Published online before print November 20, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0707498

Received for publication July 27, 2007.
Revised September 29, 2007.
Accepted for publication October 17, 2007.

Article

Essential roles of TGF- in anti-CD3 antibody therapy: reversal of diabetes in nonobese diabetic mice independent of Foxp3⁺CD4⁺ regulatory T cells

Guojiang Chen ^*, Gencheng Han ^*, Jianan Wang ^*, Renxi Wang ^*, Ruonan Xu ^*, Beifen Shen ^*, Jiahua Qian , and Yan Li ^*@

*Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China; and Vaccine Branch, National Cancer Institute, Bethesda, Maryland, USA

^@ To whom correspondence should be addressed. E-mail: liyan62033{at}yahoo.com.cn.

Abstract

Anti-CD3 mAb have potentials to treat overt autoimmunity as reported recently. However, the underlying mechanisms remain unclear. In this report, using an animal model of type 1 diabetes, we found that TGF-1, an important immunoregulatory cytokine, plays a critical role in anti-CD3-mediated diabetes reversion and immune tolerance. Anti-CD3 treatment increased the TGF-1 production, lasting for a long period of time, which contributed to maintaining peripheral tolerance by controlling pathogenic cells. Furthermore, we found that anti-CD3 treatment did not increase the forkhead box p3+ (Foxp3⁺)CD4⁺ regulatory T cells (Tregs). When fractionated from anti-CD3-treated, remitting mice and cotransferred with splenic cells from diabetic NOD mice, these Tregs failed to inhibit diabetes development in NOD.scid mice. Moreover, we found that the depletion of these Tregs did not affect an anti-CD3-mediated, therapeutic effect and the level of TGF-1 production, which suggested that an increased level of TGF-1 may not derive from these Tregs. Thus, our data showed a dispensable role of Foxp3⁺CD4⁺ Tregs in anti-CD3 antibody-reversed diabetes in NOD mice. These findings may have an important implication for understanding the involved mechanisms responsible for immunomodulatory function of anti-CD3 antibody on autoimmune diseases.

Key Words: autoimmunity • immunotherapy • cytokine • regulatory lymphocyte

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