Human CD4+ memory T cells are preferential targets for bystander activation and apoptosis.

There is much evidence that T cells may be activated via mechanisms that act independently of direct TCR ligation. Despite this, the question of whether such forms of bystander T cell activation occur during immune responses is hotly debated. To address some outstanding questions, we set up an in vitro system within which to analyze bystander T cell activation in human T cells, in the absence of the possibility for TCR cross-reactivity. In addition, we have investigated the genetic, phenotypic, and functional characteristics of bystander-activated T cells. In this study, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially among CD4(+) memory T cells. Furthermore, bystander-activated T cells display a distinct gene expression profile. The mechanism for bystander T cell activation involves soluble factors, and the outcome is an elevated level of apoptosis. This may provide an explanation for the attrition of T cell memory pools of heterologous specificity during immune responses to pathogens such as viruses.

Bystander T cell activation--implications for HIV infection and other diseases.

T cells are subject to tight regulatory measures, as uncontrolled responses might be detrimental to the host. Control measures include central or thymic tolerance, and peripheral tolerance mechanisms acting after naive T cells have encountered their cognate antigen, such as anergy induction, the contraction phase (whereby the majority of the expanded effector population undergoes apoptosis), and the action of regulatory T (Treg) cells. However, bystander T-cell activation circumvents the requirement for specific T-cell receptor stimulation, enabling T cells to bypass certain control checkpoints. The physiological relevance of the phenomenon is the subject of much controversy. This article argues that although of little consequence in the healthy individual, bystander activation could have a devastating impact in the context of disease. We focus on HIV and infection-triggered autoimmune disease as examples.