Ascorbate and TET2 couple balanced hematopoiesis to disease tolerance

Infections stimulate myelopoiesis but this comes at the cost of reduced production of other lineages. It is unclear if this imbalance is protective or damaging, and if factors that promote balanced hematopoiesis can impact infection pathology. Here we show that the ascorbate-TET axis limits excessive myelopoiesis, promotes balanced hematopoiesis, and is essential for surviving malaria. Hematopoietic-specific ascorbate depletion promoted myelopoiesis. The effects of ascorbate were mediated by TET2/TET3 activity in myeloid progenitors. Combined ascorbate and TET2 depletion markedly skewed hematopoiesis to the myeloid lineage and impaired erythropoiesis. Ascorbate is commonly depleted in infections, but the functional significance of this remains unclear. In the absence of ascorbate and TET2, mice infected with Plasmodium parasites could clear the pathogen, but had exacerbated myeloid and impaired erythroid response, anemia, and tissue damage and they succumbed to infection, indicating compromised disease tolerance. Therefore ascorbate and TET2 promote balanced hematopoiesis to impart tolerance to malaria.