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

Abstract

Autoimmune and other chronic inflammatory diseases (AID) are prevalent diseases which can severely impact the quality of life of those that suffer from the disease. In most cases, the etiology of these conditions have remained unclear. Immune responses that take place e.g. during natural infection or after vaccination are often linked with the development or exacerbation of AID. It is highly debated if vaccines induce or aggravate AID and in particular adjuvants are mentioned as potential cause. Since vaccines are given on a large scale to healthy individuals but also to elderly and immunocompromised individuals, more research is warranted. Non-specific induction of naïve or memory autoreactive T cells via bystander activation is one of the proposed mechanisms of how vaccination might be involved in AID. During bystander activation, T cells unrelated to the antigen presented can be activated without (strong) T cell receptor (TCR) ligation, but via signals derived from the ongoing response directed against the vaccine-antigen or adjuvant at hand. In this study we have set up a TCR transgenic T cell transfer mouse model by which we were able to measure local bystander activation of transferred and labeled CD4+ T cells. Intramuscular injection with the highly immunogenic Complete Freund’s Adjuvant (CFA) led to local in vivo proliferation and activation of intravenously transferred CD4+ T cells in the iliac lymph node. This local bystander activation was also observed after CFA prime and Incomplete Freund’s Adjuvant (IFA) boost injection. Furthermore, we showed that an antigen specific response is sufficient for the induction of a bystander activation response and the general, immune stimulating effect of CFA or IFA does not appear to increase this effect. In other words, no evidence was obtained that adjuvation of antigen specific responses is essential for bystander activation.

Laser‐facilitated epicutaneous immunotherapy with depigmented house dust mite extract alleviates allergic responses in a mouse model of allergic lung inflammation

“…This closely resembles the effects seen after immunotherapy in humans . While treatment had a strong boosting effect on total serum IgE (Figure C), there was only little difference in HDM‐specific IgE between treatment and untreated groups (Figure D), indicating the generation of IgE against nonrelated antigens due to a bystander effect . In all cases, EPI 100 induced the lowest levels of therapy‐associated total as well as HDM‐specific IgE.…”

NLGP Attenuates Murine Melanoma and Carcinoma Metastasis by Modulating Cytotoxic CD8+ T Cells

“…Interestingly, a similar observation was also made by LiebundGut-Landmann et al, where CD8 + T cell proliferation only occurred by curdlan-induced dectin-1-activated DCs in the presence of antigen (43). Overall, the stringent requirement of antigen in CD8 + T cell activation by dectin-1-induced DC reduced the chances of bystander immunotoxicity, which occurs with many immunotherapeutic drugs (49,50). On the other hand, this particular feature theoretically predicts that NLGP will be beneficial for a tumor with multiple antigens such as melanoma but may not be beneficiary against tumor with minimal tumor antigen.…”

Outer Membrane Protein of Gut Commensal Microorganism Induces Autoantibody Production and Extra-Intestinal Gland Inflammation in Mice

“…Stimulation with PGN, MDP, LTA, or LPS did not induce infiltration of inflammatory cells in the Harderian or salivary glands. It may be possible that the molecules did not possess the combined functionality of immunogenic antigens and bystander adjuvants [ 37 ], which are indispensable for autoimmunity [ 38 ]. In addition to the microbial molecules investigated in the present study, we previously studied the flagellar filament structural protein FliC, a TLR5-ligand, and an NLR apoptosis inhibitory protein (NAIP) activator, derived from commensal E. coli , which was repeatedly inoculated following the same regimen of injection as the present study [ 17 , 39 ].…”