The death receptor Fas mediates a non-apoptotic signaling cascade in apoptosis resistant CD4+ T cells via the MAPK pathway. (P1304)

Abstract

Abstract The Fas death receptor mediates peripheral tolerance by apoptotic deletion of autoreactive T cells through Restimulation Induced Cell Death (RICD). Previously, we have shown that within a pool of T cells, effector memory were more sensitive to Fas-induced apoptosis than activated naïve CD4 T cells due to efficient DISC formation. Recently, we found that FasL induces an early MAPK response in the form of pJNK activation, preferentially in activated naïve, but not memory T cells. In apoptosis resistant FADD or Caspase-8 deficient Jurkat T cells, the pJNK response is exaggerated indicating that in the absence of a functional Fas apoptotic response, an alternate non-apoptotic pathway is elicited. Further, in HH cells, a CTCL resistant to Fas apoptosis, pJNK activation was upregulated when compared to HUT78, a highly apoptosis sensitive cell line. In an attempt to identify the upstream activators of Fas-induced pJNK, we studied the role of the kinase RIP1, a known component of the Fas DISC. Inhibition of RIPK1 decreased pJNK activation in Jurkat cells and RIP deficient Jurkat cells were unable to activate pJNK upon FasL stimulation. Immunoprecipitation studies also indicated a preferential recruitment of RIPK1 to the Fas DISC in apoptosis resistant T cells. These preliminary results indicate a role for Fas mediated non-apoptotic MAPK signaling in early activated naïve T cells that precedes its traditional apoptotic role in the elimination of effector memory cells.