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 which 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 analyse 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. Here, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially amongst 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. Three conditions tested with 4 biological repilicates in each: Resting cells - cells expressing a TCR which does not specifically recognize SEB (Vβ13.1 T cells) and did not upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Bystander activated cells - cells expressing a TCR which does not specifically recognize SEB (Vβ13.1 T cells), but which did upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Directly activated cells - cells expressing a TCR which is known to specifically recognize SEB (Vβ17 T cells), and which did upregulate the activation marker CD25 in response to direct SEB stimulation over a 5 day period.