Mitochondria-centric activation induced cell death of cytolytic T lymphocytes and its implications for cancer immunotherapy

Abstract

Premature death of the adoptively transferred cytolytic T lymphocytes (CTL) by means of activation induced cell death (AICD) represents one of the major constraints in devising an effective anti-cancer immune intervention strategy. Understanding the mechanism of AICD is, therefore, critical for developing methods to interfere with this death process. Although the existing paradigm on AICD centers around the initiation of the cascade of events originating from the engagement of death receptors leading to the activation of effector caspases and eventually resulting in cell death, recent findings have questioned the universal role of caspases as the cell death executioners. We here review our current understanding of the contribution of caspase-dependent and caspase-independent death executioners in AICD of T cells. We will also discuss the involvement of mitochondria-centric death pathway in AICD of human tumor associated antigen-specific primary CTL and its implications in cancer immunotherapy.

Figure 1. Kinetics of an antigen specific T cell response

As shown an antigen specific T cell response in comprised of three distinct phases: expansion, contraction, and memory.

Figure 2. Extrinsic and Intrinsic T cell death pathways

(Left Panel). The existing paradigm (left panel) states that the T cell death is triggered by the engagement of the surface expressed death receptors (DR) with their corresponding death ligands that leads to the activation of caspases and results in oligosomal DNA degradation mediated cell death. (Right Panel). Recent report suggest that the T cell death, especially the epitope specific activation induced cell death (AICD) in human tumor antigen specific T cells (right panel) is an intrinsic, DR-independent, mitochondria-centric process, in which JNK and mitochondria-resident death executioner, apoptosis inducing factor (AIF) play crucial roles [9,10].