Regardless of the organism in which it occurs, the immunogenic cell death process follows a similar trend: aggregation of proteins (or peptides) at a cell membrane cause damage to the cell membrane, and this damage subsequently releases natural adjuvants called damage-associated molecular patterns (DAMPs) which are natural adjuvants for the immune system. For example, Alzheimer’s Disease is a multifactorial disease of unknown etiology, but the central hypothesis is that it is triggered by an accumulation of the pathogenic peptide amyloid beta Aβ1-42 in the brain. Aβ1-42 spontaneously aggregates into soluble fibrils and oligomers, which are the primary toxic forms of Aβ1-42, and create immunogenic cell death and DAMPs release. We recently designed peptides inspired by the intermolecular interactions as in Aβ1-42 peptides and aggregate in the cellular environment, inducing a local and transient immunogenic cell death. The results of the process are akin to Aβ1-42 oligomers in terms of inducing the immune response through cell membrane rupture, which we called “peptide-aggregation induced immunogenic rupture (PAIIR)”. We showed that the preparation of a vaccine including these peptides increases protective antibody formation significantly. In this study, we showed the control over peptide assembly, as in Aβ1-42 oligomerization, to control the immune response effect of PAIIR. During peptide assembly, individual building motifs and their aggregates are in equilibrium. The concentration of building motifs must be higher than the critical aggregation concentration to trigger assembly. In living cells, due to the complexity and crowd of a cellular environment, the interaction between building motifs can be disrupted, and therefore aggregation kinetics can be modified. We followed a similar procedure to the one in nature for Aβ1-42 oligomerization and created aggregates of the PAIIR that can assemble in different kinetics. The aggregation kinetics affected their cell membrane rupture kinetics, thus their immunogenicity. The immune response of these aggregates showed significant differences, correlated to their aggregation kinetics.

Controlling the immune response through controlling the aggregation kinetics of engineered peptides

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