Interleukin-27-Producing CD4+ T Cells Regulate Protective Immunity during Malaria Parasite Infection

Interleukin-27 (IL-27) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4+ T cells that produce IL-27 in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4+ T cells were Foxp3−CD11a+CD49d+ malaria antigen-specific CD4+ T cells and were distinct from interferon-γ (IFN-γ) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4+ T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4+ T cells and their critical role in the regulation of the protective immune response against malaria parasites. [Display omitted] •Foxp3−CD4+ T cells can produce IL-27 during infection with malaria parasites•IL-27-producing CD4+ T cells are distinct from IFN-γ- or IL-10 producing cells•IL-27-producing CD4+ T cells inhibit IL-2 production and T cell proliferation•CD4+ T cells are the major source of IL-27 during malaria infection IL-27 is a heterodimeric regulatory cytokine produced by antigen-presenting cells. Yui and colleagues report that malaria-specific CD4+ T cells, distinct from Th1 and Tr1 cells, produce IL-27 that inhibits alternate cellular IL-2 production and clonal expansion, suggesting that unique regulatory T cells are induced during malaria infection.