TNFR1 signaling drives the immunosupressive function of MDSC during Staphylococcus aureus sepsis.

LEDO C; GOMEZ MI; GONZALEZ C; PONCINI C

Waterville Valley, New Hampshire

Conferencia; GRC Staphylococcal Diseases; 2017

GORDON RESEARCH CONFERENCES

TNF-α signaling is strongly associated with the inflammatory response that characterizes the inicial phase of sepsis. The events that govern the concommitant and subsequent immunosupression, however, are not completely elucidated. Myeloid derived supressor cells (MDSC) have been described as an immature population of cells that is able to supress T cell responses in polymicrobial sepsis and during chronic and persistant Staphylococcus aureus infeccions. It has been described that TNF-α participates in MDSC accumulation and activation during chronic inflammation.The aim of this study was to determine the role of MDSC and TNFR1 signaling in the modulation of T cell function during S. aureus sepsis. We used a murine model of S. aureus sepsis of peritoneal origin. In this model the onset of sepsis was characterized by a high rate of bacteriemia at 4 hours after inoculation of S. aureus. Significant weight loss was also observed and a 10% of mortality that ocurred during the first 48 hours was recorded. In addittion, significantly increased levels of IL-6, which have been associated to the severity of sepsis in humans and in animal models, were found in serum at 4 hours post-inoculation. At day 8 after inoculation, surviving mice developed splenomegaly and increased levels of IL-10 in plasma and spleen, characteristic of the immunospresive phase of sepsis, were observed. At this time point significantly reduced T cell responses, particularly in CD4+ cells, mesured as the proliferative capacity in response to ConA, were observed in S. aureus infected mice compared with control mice. The percentage and number of MDSC accumulated in the spleen of septic mice was significantly increased compared with control mice. IFN-gamma production quantified in the proliferation assays significantly correlated with the percentage of MDSC present in the spleen of septic mice suggesting a role for this population in the T cell dysfunction in the spleen. Treatment of septic mice with 5´Fluorouracil, at a dose proven to specifically deplete MDSC, not only reduced the number of these cells in the spleen but also significantly improved the proliferative capacity of CD4+ T cells. To evaluate the role of TNFR1 in the accumulation and supressive function of MDSC, S. aureus sepsis was induced in tnfr1 -/- mice. In this group, the incidence of bacteriemia and distal organ colonization as well as the plasmatic levels of IL-6 were equivalent to those in the wild type group. However, these mice did not show increased levels of IL-10 in plasma or spleen. At day 8 after inoculation, a significant increase in the percentage and number of MDSC in the spleen was observed. Nonetheless, the proliferative capacity of CD4+ T cells did not differ from that of control mice (inoculated with PBS) suggesting that in the abscense of TNFR1 signaling MDSC might lose their suppressive capacity. MDSC are known to exert their suppressive function trough the expression of arginase 1 and iNOS. Therefore, we evaluated the expression of these enzymes in MDSC purified from the spleen of wild type and tnfr1 -/- at day 8 after the onset of sepsis. The levels of arg1 and iNOS were decreased in MDSC from tnfr1 -/- compared with MDSC from wild type mice. The inflammatory proteins S100A8 and S100A9, that had been suggested to inhibit MDSC maturation, were expressed in both tnfr1 -/- and wild type mice. Taken together these results indicate that MDSC contribute to T cell dysfunction during S. aureus sepsis and that TNFR1 signaling determines the suppresive capacity of these cells highliting the role of TNF in both the inflammatory and the immunosupressive phases of staphylococcal sepsis.