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Innate immune system favors emergency monopoiesis at the expense of DC-differentiation to control systemic bacterial infection in mice

Pasquevich, K. A., Bieber, K., Gunter, M., Grauer, M., Potz, O., Schleicher, U., Biedermann, T., Beer-Hammer, S., Buhring, H. J., Rammensee, H. G., Zender, L., Autenrieth, I. B., Lengerke, C., Autenrieth, S. E. (2015).

Eur J Immunol. 2015 Oct;45(10):2821-33. doi: 10.1002/eji.201545530. Epub 2015 Jul 24.

DCs are professional APCs playing a crucial role in the initiation of T-cell responses to combat infection. However, systemic bacterial infection with various pathogens leads to DC-depletion in humans and mice. The mechanisms of pathogen-induced DC-depletion remain poorly understood. Previously, we showed that mice infected with Yersinia enterocolitica (Ye) had impaired de novo DC-development, one reason for DC-depletion. Here, we extend these studies to gain insight into the molecular mechanisms of DC-depletion and the impact of different bacteria on DC-development. We show that the number of bone marrow (BM) hematopoietic progenitors committed to the DC lineage is reduced following systemic infection with different Gram-positive and Gram-negative bacteria. This is associated with a TLR4- and IFN-gamma-signaling dependent increase of committed monocyte progenitors in the BM and mature monocytes in the spleen upon Ye-infection. Adoptive transfer experiments revealed that infection-induced monopoiesis occurs at the expense of DC-development. Our data provide evidence for a general response of hematopoietic progenitors upon systemic bacterial infections to enhance monocyte production, thereby increasing the availability of innate immune cells for pathogen control, whereas impaired DC-development leads to DC-depletion, possibly driving transient immunosuppression in bacterial sepsis.