Molecular and Metabolic Regulation of Cell Death in CD8+ T Cell Subsets
Abstract
Cellular CD8+ T cell immunity is responsible for fighting intracellular pathogens and generating a long lasting memory pool for improved control of subsequent infections. During primary and secondary T cell responses, activated effector T cells rapidly proliferate to control an invading pathogen. However, T cell expansion must be constrained and counterbalanced through programmed cell death to cull excess cells and prevent unintended collateral damage to the host. Two major pathways of programmed cell death eliminate activated effector T cells: restimulation induced cell death (RICD) and cytokine withdrawal induced cell death (CWID). The primary focus of this work was to define new molecular and metabolic determinants of differential apoptosis sensitivity via comparative analysis of primary human CD8+ T cells. First, we identify a critical role for diacylglycerol kinase alpha (DGK alpha) in modulating TCR signaling in SAP-deficient T cells, which we previously showed are resistant to RICD. Loss of the adaptor protein SAP causes X-linked lymphoproliferative disease (XLP-1). Without SAP, we found that hyperactive DGK alpha depleted the key second messenger diacylglycerol, attenuating the TCR signal below the threshold required to induce expression of specific pro-apoptotic molecules of the nuclear-orphaned receptor family. Importantly, we showed that pharmacological inhibition of DGK alpha restored RICD sensitivity in primary XLP-1 patient T cells. This work offers a new therapeutic approach for reversing acute, often lethal CD8+ T cell accumulation. Second, we describe here a direct influence for glycolytic metabolism on RICD sensitivity of CD8+ effector T cells. Specifically, acute glucose availability and active glycolysis promoted de novo expression of Fas-ligand after TCR restimulation. For the first time, these data indicate an explicit role for metabolic reprogramming in licensing RICD in activated effector T cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 04, 2016
- Accession Number
- AD1069890
Entities
People
- Sasha E. Akins
Organizations
- Uniformed Services University of the Health Sciences