title: 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.
authors.affiliation: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India.
authors.forename: Doureradjou
authors.initials: D
authors.lastname: Peroumal
authors.affiliation: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India.
authors.forename: Thiruvaimozhi
authors.initials: T
authors.lastname: Abimannan
authors.affiliation: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India.
authors.forename: Ravichandra
authors.initials: R
authors.lastname: Tagirasa
authors.affiliation: Institute of Medical Sciences & SUM Hospital, Kalinga Nagar, Bhubaneswar, Odisha, India.
authors.forename: Jyothi Ranjan
authors.initials: JR
authors.lastname: Parida
authors.affiliation: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Kalinga Institute of Medical Sciences, Patia, Bhubaneswar, Odisha, India.
authors.forename: Prasantha
authors.initials: P
authors.lastname: Padhan
authors.affiliation: Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India.
authors.forename: Satish
authors.initials: S
authors.lastname: Devadas
mesh_terms: D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015550:Cell Degranulation; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000032:analysis*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: AICD; FasL; Immune response; Immunity; Immunology and Microbiology Section; MAPK; T helper cells; rheumatoid arthritis