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Abstract
Activation Induced Cell Death of T helper cells is central to maintaining immune homeostasis and a perturbation often manifests in aberrant T helper cells that is associated with immunopathologies. Significant presence of T cells positive for IL-17A (Th17) and dual positive for IFN-γ/IL-17A (Th1/Th17) in both effector (CD45RA+RO+) and memory (CD45RA−RO+) compartments with differential FasL protein in RA peripheral blood suggested their differential TCR AICD sensitivity. Lowered active caspase-3 in Th17 and Th1/Th17 over Th1 cells confirmed their capability to resist AICD and pointed to early upstream events. Differential MAPK activities, FasL protein and downstream caspase-3 activities in murine Th1 and Th17 cells established distinct TCR mediated signaling pathways and suggested low Erk and p38 activity as pivotal for AICD sensitivity. We extrapolated our mouse and human data and report that Fas-FasL is the preferred death pathway for both Th1 and Th17 and that inherently low Erk2 activity protected Th17 cells from TCR AICD. The presence of significantly higher numbers of aberrant T helper cells in RA also suggest an inflammatory cytokine milieu and AICD insensitive T cell link to sustained inflammation. Re sensitization to apoptosis by targeting MAPK activity especially Erk2 in RA might be of therapeutic value.
Highlights
Rheumatoid arthritis (RA) is a severe debilitating inflammatory joint disease with unknown etiology
We report the exclusive presence of significantly elevated IL-17A+ (Th17) and the dual IFN-γ/IL17A+ (Th1/Th17) phenotypes in both the memory and effector compartments of RA patients (Figure 1B-1C)
These results strongly suggest that inflammation in RA might maximally be contributed by the significant presence of IL-17A secreting Th17 and IFN-γ/IL-17A secreting T helper 1 (Th1)/ Th17 cells in both effector and memory compartments
Summary
Rheumatoid arthritis (RA) is a severe debilitating inflammatory joint disease with unknown etiology. The prevalence is approximately 1% of the world’s population and affects women three times more than men [1] The hallmark of this disease are episodic chronic inflammation, joint swelling and progressive joint destruction mediated largely in part by inflammatory T helper cells [2]. The inability of IL-12p35 antibody to block the development of autoimmune arthritis and the exaggerated Immune pathology in IFN-γ KO suggested a dampening role for IFN-γ [9,10,11] These and other studies show that the absence of IFN-γ exacerbated the disease severity in many IL-17 mediated autoimmune diseases including RA [3, 8, 9] while other recent reports still suggest a role for www.impactjournals.com/oncotarget
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