CD4 Dependent Signaling Regulates T-helper Effector Functions and Cell Death
Open AccessActivation induced cell death, AICD, is an important mechanism for the elimination of clonally expanded T cells in response to antigenic challenge. In chronic infections AICD is mediated by the FasR. However, the signaling that occurs in response to T cell activation that increases the cell's susceptibility to FasR-mediated cell death, frequently referred to as the competency to die signal, is unknown. We have shown that MHC class II-restricted T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene have a defect in Th2 effector functions and that this is related to a defect in AICD. These studies suggest that the CD4 co-receptor is in part, responsible for the competency to die signal. Here we report two mechanisms explaining CD4 regulation of AICD. First, mutant CD4 T cells demonstrate defective death inducing signaling complex assembly as shown by decreased recruitment of FasR and caspase 8 into lipid rafts following antigen stimulation. Secondly, mutant CD4 T cells produce less IL-2 in response to peptide re-stimulation and that exogenous IL-2 during re-stimulation restores partial susceptibility of mutant CD4 T cells to AICD. Importantly, IL-2 production and proliferation after primary peptide stimulation is comparable between WT and mutant CD4 T cells suggesting a novel role for CD4 in regulating T cell effector functions. Furthermore, we show that the role of CD4 in regulating effector T cells is very important as CD4 mutant T cells are equally susceptible to plate-bound anti-CD3 AICD as wild-type and that IL-2 production in response to anti-CD3 is comparable between wild-type and mutant CD4 T cells. These data suggest that CD4-dependent signaling events may protect against the decreased IL-2 production and resistance to activation induced cell death seen during T cell senescence and exhaustion associated with chronic immune stimulation.
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