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Published online before print May 13, 2008

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(Journal of Leukocyte Biology. 2008;84:480-487.)
© 2008 by Society for Leukocyte Biology

Costimulatory effects of IL-1 on the expansion/differentiation of CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25⁺Foxp3^– T cells

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

² Correspondence: LI/NIAID/NIH, Building 10, Room 11N315, 10 Center Drive-MSC 1892, Bethesda, MD 20892, USA. E-mail: eshevach{at}niaid.nih.gov

CD4⁺CD25⁺forkhead box p3 (Foxp3)⁺ regulatory T cells (Treg) control peripheral tolerance. Although Treg are anergic when stimulated through the TCR, mature bone marrow-derived, but not splenic, dendritic cells (DC) can induce their proliferation after TCR stimulation in the absence of IL-2. One possibility is that the DC produce proinflammatory cytokines such as IL-1 or IL-6 that function as growth factors for Treg. We have analyzed the costimulatory effects of IL-1 on the expansion of Foxp3⁺ Treg in vitro. When CD4⁺CD25⁺ T cells were cultured in the presence of splenic DC and IL-1, marked expansion of the Foxp3⁺ T cells was observed. The effects of IL-1 were mediated on CD4⁺CD25⁺Foxp3^– T cells present in the starting population rather than on the DC or on the CD4⁺CD25⁺Foxp3⁺ T cells. In contrast, stimulation of CD4⁺CD25⁺ T cells with plate-bound anti-CD3 and IL-1 in the absence of DC resulted in the outgrowth of a CD4⁺CD25⁺Foxp3^– T cell population composed of NKT cells and non-NKT, IL-17-producing cells. Foxp3⁺ Treg purified from mice expressing the reporter gene enhanced GFP in the Foxp3 locus failed to proliferate when costimulated with IL-1. These findings have important implications for the design of protocols for the expansion of CD4⁺CD25⁺ T cells for cellular biotherapy.

Key Words: rodent • dendritic cells • costimulation • cell proliferation