Hematopoietic stem cells undergo an IFNγ-dependent, MyD88-independent transition from dormancy to activity during acute bacterial infection (153.8)

Abstract

Abstract How hematopoietic stem cells (HSCs) respond to and recover from immunologic stress is not well-understood. We demonstrate that infection with the intracellular bacteria, Ehrlichia muris, induces a transient expansion of bone marrow Lin-negative Sca-1+ cKit+ (LSK) progenitor cells. As inflammation can modulate the expression of surface markers used to phenotype stem and progenitor cells, we addressed whether the phenotypic changes correlated with functional changes in the progenitor cell population. The expansion of LSK cells was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation. The infection-induced changes required IFNγ signaling, and were accompanied by an expansion of more differentiated multipotent progenitor cells. IFNγ was required for the infection-induced loss of functionally-defined dormant HSCs in label retaining-cell assays. In competitive reconstitution experiments, LSK cells purified from infected IFNγR-deficient mice preferentially engrafted, relative to LSK cells purified from infected wild type mice. Furthermore, the infection-induced changes in progenitor cells were independent of intrinsic MyD88-signaling. We propose that IFNγ elicited during acute infection, provides a signal to dormant HSCs to undergo a rapid transition from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense.