Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance

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.

Autoreactive T Cells in Immunopathogenesis of TB-Associated Uveitis

“…Our previous work on CD4 þ T cells from the peripheral blood of rheumatoid arthritis patients demonstrated that an inherently low MAPK activity, particularly ERK1/2, protects Th17 cells from AICD. 26 We could validate those results in TBU, because we found that ERK1/2 activity was significantly lower in the autoreactive T cells compared with the ESAT-6-specific population (Figs. 5A, 5B).…”

Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses

“…As shown by Song et al, pore formation by alpha-toxin allows Ca 2+ ions to enter the cell and induce downstream signaling (39), which could explain the abovementioned cytokine production upon stimulation of human T cells with sublytic concentrations of alpha-toxin (22,23). In the same line, enhanced Ca 2+ signaling might result in increased activation-induced cell death in Th1 cells, as these cells were reported to be more susceptible to Ca 2+ signaling when compared to Th17 cells due to differential Fas ligand and c-FLIP expression as well as activity of p38 and ERK (40)(41)(42). Interestingly, we could mimic the differential effects of alpha-toxin on Th1-and Th17-polarized cells using Ionomycin, suggesting an increased susceptibility toward Ca 2+ signaling in Th1 cells as mechanism underlying the differential susceptibility toward alpha-toxin-induced cell death.…”

Research Progress on the Effect of Traditional Chinese Medicine on Signal Pathway Related to Premature Ovarian Insufficiency

“…The Fas/FasL pathway, also known as the death receptor pathway, acts as an apoptotic signaling receptor, forming a death-inducing complex by binding to its ligand FasL and activating its downstream caspase-3 to induce apoptosis [ 37 ].…”