Oncotarget

Research Papers: Immunology:

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

Doureradjou Peroumal, Thiruvaimozhi Abimannan, Ravichandra Tagirasa, Jyothi Ranjan Parida, Santosh Kumar Singh, Prasantha Padhan and Satish Devadas _

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Oncotarget. 2016; 7:54339-54359. https://doi.org/10.18632/oncotarget.10913

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Abstract

Doureradjou Peroumal1, Thiruvaimozhi Abimannan1, Ravichandra Tagirasa1, Jyothi Ranjan Parida3, Santosh Kumar Singh1, Prasantha Padhan2 and Satish Devadas1

1 Infectious Disease Biology, Institute of Life Sciences, Chandrashekarpur, Bhubaneswar, Odisha, India

2 Kalinga Institute of Medical Sciences, Patia, Bhubaneswar, Odisha, India

3 Institute of Medical Sciences & SUM Hospital, Kalinga Nagar, Bhubaneswar, Odisha, India

Correspondence to:

Satish Devadas, email:

Keywords: T helper cells, MAPK, AICD, FasL, rheumatoid arthritis, Immunology and Microbiology Section, Immune response, Immunity

Received: October 29, 2015 Accepted: June 20, 2016 Published: July 28, 2016

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.


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