CD8⁺ T cells and IFN-γ induce autoimmune myelofibrosis in mice

Myelofibrosis usually occurs either as a part of a myelodysplastic syndrome or in conjunction with neoplasia. It is not commonly thought of an autoimmune disease. We reported that p40^-/-IL-2Rα^-/- (interleukin-12p40 and interleukin-2 receptor alpha double knockout) mice, a mouse model of human primary biliary cholangitis, exhibited features consistent with autoimmune myelofibrosis, including anemia associated with bone marrow fibrosis, and extramedullary hematopoiesis (EMH) including LSK (Lineage^-c-Kit⁺Sca-1⁺) cells in spleen, liver and peripheral blood. There were also increased LSK cells in bone marrow but they demonstrated impaired hematopoiesis. Importantly effector memory T cells that infiltrated the bone marrow of p40^-/-IL-2Rα^-/- mice manifested a higher ability to produce IFN-γ. CD8⁺ T cells, already known to play a dominate role in portal inflammation, were also key for bone marrow dysregulation and EMH. IFN-γ was the key cytokine that induced bone marrow fibrosis, bone marrow failure and EMH. Finally anti-CD8α antibody therapy fully protected p40^-/-IL-2Rα^-/- mice from autoimmune myelofibrosis. In conclusion, our results demonstrate that CD8⁺ T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8⁺ T cells and IFN-γ as a therapeutic targets.