REPROGRAMMING OF DENDRITIC CELL PROGENITORS IN THE BONE MARROW DURING MURINE POLYMICROBIAL SEPSIS

Abstract

Polymicrobial sepsis is associated with the predominance of anti-inflammatory cytokines like IL-10 and the absence of a Th1 type response. Dendritic cells (DC) are potent antigen-presenting cells and play a key role in the induction of T cell responses. We investigated whether progenitor cells of DC in the bone marrow are modulated during sepsis in terms of DC differentiation and cytokine secretion. Twenty-four h after Cecal ligation and puncture (CLP) or sham operation, bone marrow cells were prepared and cultured in the presence of GM-CSF in order to generate bone marrow-derived DC (BMDC). BMDC were stimulated with CpG oligonucleotides and cytokine secretion was determined. In addition, CpG-stimulated BMDC were injected into healthy mice and the priming of T cells in the draining lymph nodes was analyzed in terms of IFN-γ secretion and proliferation. BMDC of septic and control mice secreted comparable amounts of TNF-α and IL-12 when stimulated with CpG. However, BMDC from septic mice released up to 3-fold more IL-10 than BMDC from sham mice. CpG-stimulated BMDC generated from sham and septic mice induced comparable Th cell proliferation in vivo. But, Th cells primed by BMDC from septic mice released 5-fold less IFN-γ. Thus, during polymicrobial sepsis, DC progenitor cells in the bone marrow are reprogrammed and give rise to DC that prevent the development of a protective Th1-type response.