Interferon-Gamma Is a Critical Regulator of the Hematopoietic Stem Cell Response to Chronic Infection.

Abstract 2549

Poster Board II-526

Hematopoietic stem cells (HSCs) are the progenitors of all blood cells including the effector cells of the immune system. HSCs remain dormant during most of the life of an organism, but can be activated by stress conditions to replenish peripheral blood cells. Infection is a common stress that leads to the consumption of immune cells, and the bone marrow must compensate for increased immune system demands by increasing production of downstream progeny during chronic infection. How this compensation is accomplished is poorly understood.

We investigated the HSC response to chronic infection using an in vivo mouse model of Mycobacterium avium (M. avium) infection. We found that infection stimulates changes in multiple hematopoietic progenitor compartments to maintain peripheral blood homeostasis. Infection activates the HSC itself to differentiate and proliferate, as measured by BrdU incorporation. Since interferon-gamma (IFNg) levels are high during M. avium infection, we hypothesized that this cytokine may be an important mediator of the HSC response. We confirmed that IFNg levels in the bone marrow, where the HSC resides, are elevated in infected mice. Consistent with our hypothesis, we found that the proliferative response to M. avium infection is abrogated in Stat1-deficient and IFNg-receptor-deficient mice, but is unaffected in IFNa-receptor-deficient mice, indicating that the HSC response to M. avium infection is critically mediated by IFNg.

To determine if IFNg alone is sufficient to stimulate the HSC, we tested and confirmed that HSCs express the IFNg receptor, and are thus capable of responding directly to IFNg signaling. We next established that IFNg stimulates expression changes in known IFN regulatory molecules such as Stat1 and Irf9 in the HSC. In agreement with our findings using M. avium, IFNg alone causes HSCs to proliferate both in vitro and in vivo, as assessed by BrdU incorporation. Furthermore, we found that HSCs from an IFNg-deficient mouse model exhibit decreased baseline proliferation and superior engraftment in a competitive transplantation assay. Thus, IFNg participates in maintaining balance between quiescence and proliferation of HSCs even in the absence of infection.

Despite historical data that IFNs are suppressors of bone marrow function, this report signifies the first in vivo evidence that IFNg has a powerful and direct effect on HSC proliferation. Thus it appears that IFN regulation of the bone marrow is a complex, and perhaps context-dependent, phenomenon. These findings inform our understanding of HSC biology as well as our ability to treat patients affected by chronic infections, such as HIV and tuberculosis, illnesses that can be complicated by bone marrow suppression.