The immunoregulation of interleukin-27 in African trypanosome infection

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Interleukin (IL)-27 is a cytokine with diverse impacts on regulation of vertebrate T helper Type 1 (Th1) responses. Initially, it was predicted as a promoter of Th1 responses. However, it was lately identified as a potent negative regulator of T cell responses in a variety of disease models, including infection with viruses, bacteria, and intracellular parasites. The extracellular protozoan parasites, African trypanosomes, cause a chronic debilitating disease associated with persistent inflammation. Using this infection model, we aim to identify novel immunoregulatory functions of IL-27 on innate and adaptive immunity. Here we demonstrate that IL-27 receptor deficient (IL-27R-/-) mice infected with African trypanosomes display excessive production of IFN-γ by CD4+ T cells, exacerbated liver pathology, and dramatically shortened survival as compared with infected wild-type mice. Depletion of CD4+ T cells or neutralization of IFN-γ ameliorates the liver pathology and extends the survival of infected IL-27R-/- mice.

Our further interest is in deciphering the mechanisms of how CD4+ T cells and IFN-γ shape the monocyte-featured innate immunity in African trypanosome infected IL-27R-/- mice. Blood monocytes typically consist of a heterogenous population of Ly6C+ and Ly6C- monocytes. Ly6C+ monocytes can give rise to inflammatory TNF-α/iNOS producing dendritic cells (Tip-DCs) and anti-inflammatory macrophages. Here we find that IL-27R-/- mice exhibit a higher frequency of Ly6C+ monocytes recruitment to the liver, where they preferentially differentiate into Tip-DCs. This is coincided with impaired development of Ly6C- monocytes and macrophages in the liver. Depletion of CD4+ T cells or neutralization of IFN-γ in infected IL-27R-/- mice diminishes the recruitment of Ly6C+ monocytes, and their differentiation into Tip-DCs in the liver. This is accompanied by the greatly enhanced counts of Ly6C- monocytes and macrophages following antibody treatments. Further evidences show that 1) IFN-γ produced by CD4+ T cells induces cell death of Ly6C- monocytes which perturb the development of Tip-DCs in infected IL-27R-/- mice and 2) cell intrinsic IFN-γ signaling drives Ly6C+ monocytes to differentiate into Tip-DCs in infected IL-27R-/- mice. Thus, our data identify IL-27 signaling as a novel immunoregulator to prevent Ly6C+ monocytes from differentiation into Tip-DCs through suppressing CD4+ T cells to secrete IFN-γ.