CD80 for lethality and CD86 for protection may lie in their relative affinities and binding kinetics for their ligands, CD28 and CTLA4, with CD80 having a relative higher affinity for CTLA4. Thus we cannot discount a potentially protective role for a CTLA4-CD86 interaction which is unmasked by the absence of CD80 in our system. This is a distinct possibility given the ability of CTLA4 to both inhibit CD28 engagement as well as direct induce signaling, including induction of tryptophan catabolism. Investigators have also described a CD28/CTLA4 independent ligand for CD86, which may also modulate our system both signaling via the receptor and ligand. Addressing both of these possibilities will be the subject of further studies. PF-3084014 Finally, it is highly probable, that the role of CD86 may indeed be tissue compartment specific. In our previous study, we noticed differential regulation of CD86 in blood and peritoneal lavage. This most likely explains the differential cytokine response, especially IL-10, between these differing compartments. However, we are still unable to provide a mechanism for this differential compartment specific regulation. However, there are many important limitations to our study. Most notably is the use of a highly lethal form of polymicrobial sepsis in our murine model. It is well established that there are multiple phases to the immune response in sepsis, with the early phases dominated by massive pro-inflammatory cytokine production, and the DMXAA latter phase by immunoparalysis. It is likely, that during the transition to these latter stages, a more prominent role for CD86 could be observed. In addition, the mechanism for loss of CD86 expression also remains incompletely understood. Whether this results in a true loss of expression or recruitment of additional low expressing CD86 monocytes from the bone marrow is also unclear. Future studies will be required to address these questions. Finally, while our data now suggest IRAK-M may be capable of differentially regulating CD80 and CD86 mediated cellular activation, there are still multiple limitations to this data. Most notably, is we can not explain the reason for the differential affinity for
