Human CD4+ Memory T Cells Are Preferential Targets for Bystander Activation and Apoptosis

Abstract

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 stimulation of activated CD4+ T cells of unrelated specificity following a booster vaccination with tetanus toxoid

“…Furthermore, infusion of LPS, which mimics bacterial infections, induces indirect activation of T cells in healthy volunteers [12], confirming similar results observed in mouse models [13,14]. In vitro, human CD4 1 memory T cells appear to be preferential targets for bystander activation, generating a distinct gene expression profile and elevating levels of the extrinsic pathway of apoptosis [15].…”

Experimental food allergy to peanut enhances the immune response to house dust mite in the airways of mice

“…The mechanism of bystander stimulation is a phenomenon primarily described for CD8 + T cells [15,16], but which has also been clearly demonstrated for CD4 + T cells [17,18]. Factors produced during the primary and secondary antigen-specific response, such as IL-2 and IL-15, activate unrelated effector CD4 + T cells [18]. As the mediastinal lymph nodes drain both the lung and the peritoneum [19], the i.p.…”

“…It is tempting to speculate that unspecific bystander activation of HDMspecific T cells by these circulating PE-specific T cells has led to a higher cytokine production by the HDMspecific T cells. The mechanism of bystander stimulation is a phenomenon primarily described for CD8 + T cells [15,16], but which has also been clearly demonstrated for CD4 + T cells [17,18]. Factors produced during the primary and secondary antigen-specific response, such as IL-2 and IL-15, activate unrelated effector CD4 + T cells [18].…”

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

“…It is believed that most of these cells are activated by nonspecific mechanisms, including cross-reactivity and cytokine-driven activation (7,9), a phenomenon referred to as "bystander activation." Furthermore, systemic translocation of gut microbial products including LPS, owing to increased permeability of the gut epithelium, is suggested to contribute to general immune activation (10).…”