Protein conformation significantly influences immune responses to prion protein

In prion diseases, such as variant Creutzfeldt-Jakob disease normal cellular prion protein (PrP^C), a largely α-helical structure is converted to an abnormal conformational isoform (PrP^Sc) that shows an increase in β-sheet content. Similarly, the recombinant form of PrP ^C (rα-PrP) can be converted to a conformation dominated by β-sheet (rβ-PrP) by reduction and mild acidification in vitro, a process that may mimic in vivo conversion following PrP^C internalization during recycling. Despite PrP^Sc accumulation and prion propagation in the lymphoreticular system before detectable neuroinvasion, no Ab response to PrP has been detected, probably due to immune tolerance. To investigate how the immune system may respond to α- and β-PrP, we immunized Prnp^0/0 mice that are not tolerant of PrP with rα-PrP and rβ-PrP. In this study, we show that although T cells stimulated by these differently folded conformers PrP recognize similar immunodominant epitopes (residues 111-130 and 191-210) the cytokine profile in response to rα- and rβ-PrP was different. Challenge with rα-PrP elicited a strong response of IL-5 and IL-10, whereas rβ-PrP led to an early increased production of IFN-γ. In addition, immunization with rα-PrP led to production of predominantly IgG1 isotype Ab in the sera, whereas after immunization with rβ-PrP, IgG2b was significantly produced. Thus, both humoral and cellular responses to these differently folded isoforms of the same protein are different, indicating a possible involvement of Th1 and Th2 pathway activation. These differences may be exploitable diagnostically and therapeutically for prion diseases, such as variant Creutzfeldt-Jakob disease.