TET2 loss impairs MPLA-induced innate immune memory during infection and disrupts hematopoiesis via RIPK1 in mice

Ten-eleven translocation protein 2 (TET2) is commonly mutated in hematologic disorders of bone marrow failure such as myelodysplastic syndrome (MDS), and loss of TET2 is associated with poor prognosis. TET2 loss is also associated with augmented inflammation, as well as impaired innate immune responses. However, many individuals harboring mutations do not develop hematologic disorders, indicating that additional factors, such as inflammation, cooperate with TET2 loss to promote disease progression. Innate immune memory is a phenomenon in which pre-treatment with microbial ligands, including monophosphoryl lipid A (MPLA), improves innate immune function while minimizing inflammation during subsequent infection. Given the previously reported innate immune impairments attributed to TET2 loss, we tested whether MPLA could induce an innate immune response in TET2-deficient mice infected with P. aeruginosa. Moreover, due to the inflammatory role of TET2 loss, we investigated whether MPLA with infection would promote disease-related phenotypes. We found that TET2-deficient mice display impaired infection response to P. aeruginosa which is partially improved with MPLA pretreatment. Assessments of pathogenic clearance functions further showed decreased capacity in TET2-deficient innate immune cells. Moreover, TET2-defcient cells also exhibit impaired differentiation. MPLA pretreatment in infected mice promotes myeloid-biased hematopoiesis at the expense of erythroid- and megakaryocyte-biased hematopoiesis, resembling MDS-like disease progression. Intriguingly, inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) dampens the effects of TET2 loss on hematopoietic perturbation. Collectively, we find that TET2 loss impairs innate immune memory and infection responses, and MPLA with infection promotes hematopoietic skewing through RIPK1. KEY POINTS- TET2 loss increases susceptibility to infection, but immune response can be improved by MPLA-induced innate immune memory. - MPLA pretreatment and infection promotes aberrant hematopoiesis and myeloid bias in TET2 deficiency that is improved by RIPK1 inhibition.