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International Immunology Advance Access originally published online on February 13, 2008
International Immunology 2008 20(4):471-483; doi:10.1093/intimm/dxn007
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

CTLA-4·Ig converts naive CD4+CD25– T cells into CD4+CD25+ regulatory T cells

Marjaneh Razmara, Brendan Hilliard, Azadeh K. Ziarani, Youhai H. Chen and Mark L. Tykocinski

Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA

Correspondence to: M. L. Tykocinski; E-mail: mlt4{at}mail.med.upen.edu

CTLA-4·Ig was originally designed as an immunosuppressive agent capable of interfering with the co-stimulation of T cells. In the present study, we demonstrate that CTLA-4·Ig, in combination with TCR ligation, has the additional capacity to convert naive CD4+CD25– T cells into Foxp3+ regulatory T (Treg) cells, as well as to expand their numbers. The CD4+CD25+Foxp3+ Treg generated by CTLA-4·Ig treatment in vitro potently suppress effector T cells. Extending this in vivo, we show that systemic administration of CTLA-4·Ig increases the percentage of CD4+CD25hiFoxp3+ cells within mixed lymphocyte reaction-induced murine lymph nodes. Significantly, the in vitro conversion of naive CD4+CD25– T cells into Treg cells is antigen-presenting cell (APC) dependent. This finding, together with the further observation that this conversion can also be driven in vitro by an antibody that engages B7-2 ligand, suggests that CTLA-4·Ig-driven Treg induction may be predicated upon active CTLA-4·Ig to B7-2 signaling within APC, which elicits from them Treg-inducing potential. These findings extend CTLA-4·Ig's functional repertoire, and at the same time, reinforce the concept that T cell anergy and active suppression are not entirely distinct processes and may be linked by some common molecular triggers.

Keywords: co-stimulation, CTLA-4·Ig, regulatory T cells

Transmitting editor: W. Strober

Received 31 August 2007, accepted 7 January 2008.


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