IRF8 expressed in T cells regulates GM-CSF expression to control myeloid derived suppressor cell differentiation (TUM6P.955)

Abstract During hematopoiesis, hematopoietic stem cells differentiate into granulocytes and macrophages via a distinct differentiation program that is controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN Regulatory Factor 8 (IRF8) accumulate CD11b+Gr1+ myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell differentiation is not fully understood. Here we report an intriguing finding that mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8- deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient mice. Overexpression of IRF8 decreased GM-CSF in T cells. Our data determine that in addition to its intrinsic role as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to repress GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism of adaptive immune cell regulation of myelopoiesis in vivo.