Cytotoxic CD8+ T Cells Stimulate Hematopoietic Progenitors by Promoting Cytokine Release from Bone Marrow Mesenchymal Stromal Cells

• Cytotoxic T cells induce the activation of hematopoietic progenitors
• CTLs secrete IFNγ, which promotes IL-6 production by bone marrow MSCs
• IL-6 stimulates multipotent hematopoietic progenitors and myeloid differentiation
• Increased numbers of inflammatory monocytes contribute to virus control

SummaryCytotoxic CD8+ T cells (CTLs) play a major role in host defense against intracellular pathogens, but a complete clearance of pathogens and return to homeostasis requires the regulated interplay of the innate and acquired immune systems. Here, we show that interferon γ (IFNγ) secreted by effector CTLs stimulates hematopoiesis at the level of early multipotent hematopoietic progenitor cells and induces myeloid differentiation. IFNγ did not primarily affect hematopoietic stem or progenitor cells directly. Instead, it promoted the release of hematopoietic cytokines, including interleukin 6 from bone marrow mesenchymal stromal cells (MSCs) in the hematopoietic stem cell niche, which in turn reduced the expression of the transcription factors Runx-1 and Cebpα in early hematopoietic progenitor cells and increased myeloid differentiation. Therefore, our study indicates that, during an acute viral infection, CTLs indirectly modulate early multipotent hematopoietic progenitors via MSCs in order to trigger the temporary activation of emergency myelopoiesis and promote clearance of the infection.

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