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

Abstract

Antigen-specific CD4 1 T cells are central to natural and vaccine-induced immunity. An ongoing antigen-specific T-cell response can, however, influence surrounding T cells with unrelated antigen specificities. We previously observed this bystander effect in healthy human subjects following recall vaccination with tetanus toxoid (TT). Since this interplay could be important for maintenance of memory, we have moved to a mouse model for further analysis. We investigated whether boosting memory CD4 1 T cells against TT in vivo would influence injected CD4 1 TCR transgenic T cells (OT-II) specific for an unrelated OVA peptide. If OT-II cells were pre-activated with OVA peptide in vitro, these cells showed a bystander proliferative response during the ongoing parallel TT-specific response. Bystander proliferation was dependent on boosting of the TT-specific memory response in the recipients, with no effect in naive mice. Bystander stimulation was also proportional to the strength of the TT-specific memory T-cell response. T cells activated in vitro displayed functional receptors for IL-2 and IL-7, suggesting these as potential mediators. This crosstalk between a stimulated CD4 1 memory T-cell response and CD4 1 T cells activated by an unrelated antigen could be important in human subjects continually buffeted by environmental antigens.

Suppressor of Cytokine Signaling 4 (SOCS4) Protects against Severe Cytokine Storm and Enhances Viral Clearance during Influenza Infection

“…This increased number of T cells in the lungs of Socs4 R108X/R108X mice is suggestive of proliferation due to bystander activation driven by cytokines rather than antigen-driven expansion of specific T cells or stimulation of cell division by cross-reactive antigens [48], [49], [50]. Interestingly, IL-6 appears to be one of the major factors driving the spontaneous proliferation of naïve T cells (both CD8 and CD4) [51], [52], [53].…”

Bystander activation of irrelevant CD4+ T cells following antigen-specific vaccination occurs in the presence and absence of adjuvant

“…Although it might seem remarkable that the stringent antigen-specificity of the adaptive immune system can be circumvented, some hypothesized that the activation of surrounding memory T cells is actually beneficial for the immune system as it might maintain or strengthen the memory T cell repertoire [1,10,15,17]. On the other hand, bystander activation during natural infection might pose a risk as well.…”

“…Importantly, though sufficient suspected individual cases have been reported, epidemiological studies do not substantiate evident causal relationships between vaccination and AID (reviewed in [28,29]). Despite several (mouse) studies [15,30,31], reviewed in [20], it is still highly debated if and how vaccinations induce or worsen AID. A number of mechanisms, amongst which bystander activation, are suggested [2,7,18,19,32].…”

Transient global T cell activation after vaccination of rhesus macaques with a DNA-poxvirus vaccine regimen for HIV

“…Although activated CD8+ T cells are not target cells for HIV, these cells may produce cytokines that drive bystander activation of CD4+ T cells [19]. The magnitude and kinetics of CD8+ T cell activation were more variable compared to CD4+ T cells (Fig.…”