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

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-17producing 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.