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

Abstract

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.