Conventional T-bet⁺Foxp3⁻ Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection

Although interferon γ (IFN-γ) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-γ effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-γ–secreting T-bet⁺Foxp3⁻ T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10⁺IFN-γ^γ population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-γ, IL-10 production could be stimulated in IL-10⁻IFN-γ⁺ cells by further activation in vitro. In addition, experiments with T. gondii–specific IL-10⁺IFN-γ⁺ CD4 clones revealed that although IFN-γ expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4⁺ T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens.