IFN-beta inhibition of MLL1 mediates CD4 T cells impaired response and post-sepsis immunosuppression. 

 

---

Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B705
Abstract ID: 5015

Presenting Author:
Patricia Assis , Research Investigator at Univ. of Michigan Med. Sch.

Abstract:

Sepsis is a devastating disease with a high in-hospital mortality. Among the patients that survive, approximately 50% will experience long-term comorbidities and are more likely to be re-hospitalized and die due to infections. This suggests that the post-septic immune response is chronically suppressed. To study sepsis long-term effects, we used whole blood samples from a biorepository of human samples, including post-sepsis patients and splenocytes from post-septic mouse. Post-septic patients present reduced expression of MLL1 (chromatin-modifying methyltransferase enzyme) for up to five years after sepsis. Additionally, analysis of different murine cell types revealed that MLL1 is downregulate specifically in CD4 T cells. MLL1 is a key regulator of activation, proliferation and effector function of Th1 cells. Conversely, type I IFNs present immunosuppressive effects on CD4 T cells. Notably, expression of IFN-beta is chronically elevated in post-septic patients compared to health controls. Likewise, monocytes from post-septic mice also present increased expression of IFN-beta. We observed that IFN-beta have inhibitory effect on MLL1 expression in CD4 T cells both in vivo and in vitro, whereas induces MLL1 expression in monocytes. Finally, based on the present data we hypothesize that sepsis-induced IFN-beta causes reduction in MLL1 expression in CD4 T cells, which, in turn, mediates the immunosuppressive phenotype observed in post-septic individuals.