DX5+CD4+ T cells modulate cytokine production by CD4+ T cells towards IL‐10 via the production of IL‐4

CD4+ Th cells play a critical role in orchestrating the adaptive immune response. Uncontrolled Th1 responses are implicated in the pathogenesis of autoimmune diseases. T cells with immune-modulatory properties are beneficial for inhibiting such inflammatory responses. Previously we demonstrated that repetitive injections of immature DC induce expansion of DX5+CD4+ T cells, which upon adoptive transfer show potent regulatory properties in murine collagen-induced arthritis as well as in delayed-hypersensitivity models. However, their regulatory mechanism remains to be defined. Here, we analyzed the effect of DX5+CD4+ T cells on other CD4+ T cells in vitro. Although proliferation of naive CD4+ T cells upon antigenic triggering was not altered in the presence of DX5+CD4+ T cells, there was a striking difference in cytokine production. In the presence of DX5+CD4+ T cells, an IL-10-producing CD4+ T-cell response was induced instead of a predominant IFN-γ-producing Th1 response. This modulation did not require cell–cell contact. Instead, IL-4 produced by DX5+CD4+ T cells was primarily involved in the inhibition of IFN-γ and promotion of IL-10 production by CD4+ T cells. Together, our data indicate that DX5+CD4+ T cells modulate the outcome of Th-responses by diverting Th1-induction into Th responses characterized by the production of IL-10.