Abrogation and homeostatic restoration of IgE responses by a universal IgE allergy CTL vaccine-The three signal self/non-self/self (S/NS/S) theory.

ABSTRACT

Natural IgE cytotoxic peptides (nECPs), which are derived from the constant domain of the heavy chain of human IgE producing B cells via endoplasmic reticulum (ER) stress, are decorated onto MHC class 1a molecules (MHCIa) as unique biomarkers for CTL (cytotoxic T lymphocyte)-mediated immune surveillance. Human IgE exhibits only one isotype and lacks polymorphisms; IgE is pivotal in mediating diverse, allergen-specific allergies. Therefore, by disrupting self-IgE tolerance via costimulation, the CTLs induced by nECPs can serve as universal allergy vaccines (UAVs) in humans to dampen IgE production mediated by diverse allergen-specific IgE-secreting B cells and plasma cells expressing surface nECP-MHCIa as targets. The study herein has enabled the identification of nECPs, A32 and SP-1/SP-2 nonameric natural peptides produced through the correspondence principle. Vaccination using nECP induced nECP-specific CTL that profoundly suppressed human IgE production in vitro as well as chimeric human IgE production in human IgE/HLA-A2.01/HLA-B7.02 triple transgenic rodents. Furthermore, nECP-tetramer-specific CTLs were found to be converted into CD4 Tregs that restored IgE competence via the homeostatic principle, mediatepred by SREBP-1c suppressed DCs. Thus, nECPs showed causal efficacy and safety as UAVs for treating categorically type I hypersensitivity IgE-mediated allergies. The applied vaccination concept presented provides the foundation to unify, integrate through a singular class of tetramer-specific TCR clonotypes for regulaing human IgE production. The three signal theory pertains to mechanisms of three cells underlying central tolerance (S), breaking self tolerance (NS) and regaining peripheral tolerance (S) via homeostasis concerning nECP as an efficacious and safe UAV to treat type I IgE-mediated hypersensitivity. The three signal theory impirically extended, may be heuritic for immuno-regulation of adaptive immune repertoire in general.