IL-34- and M-CSF-induced macrophages switch memory T cells into Th17 cells via membrane IL-1α.

Macrophages orchestrate the immune response via the polarization of CD4(+) T helper (Th) cells. Different subsets of macrophages with distinct phenotypes, and sometimes opposite functions, have been described. M-CSF and IL-34 induce the differentiation of monocytes into IL-10(high) IL-12(low) immunoregulatory macrophages, which are similar to tumor-associated macrophages (TAMs) in ovarian cancer. In this study, we evaluated the capacity of human macrophages induced in the presence of M-CSF (M-CSF macrophages) or IL-34 (IL-34 macrophages) and ovarian cancer TAMs to modulate the phenotype of human CD4(+) T cells. Taken together, our results show that M-CSF-, IL-34 macrophages, and TAMs switch non-Th17 committed memory CD4(+) T cells into conventional CCR4(+) CCR6(+) CD161(+) Th17 cells, expressing or not IFN-gamma. Contrary, the pro-inflammatory GM-CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL-1α (mIL-1α), which is constitutively expressed by M-CSF-, IL-34 macrophages, and TAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis.