Background: The predominant proteins of the CNS are myelin basic protein, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein. PLP139-151 is one of the major encephalitogenic epitopes of PLP. The epitope PLP139-151 binds to MHC class II (I-As) of SJL/J mice and induces Th1 responses. Aim: The aim was to synthesize and test the immunological activity and cyclic analogs of PLP139-151 peptide and determine the immunological differences between adjuvant and conjugation to mannan. Materials & methods: We designed and synthesized cyclic peptides based on the linear PLP139-151 epitope by mutating critical T-cell receptor contact sites of residues W144 and H147, resulting in the mutant peptides PLP139-151, [L144, R147]PLP139-151 or cyclo(139-151)PLP139-151 and cyclo(139-151) [L144, R147]PLP139-151. In this study, mice were immunized with mutant peptides either emulsified in complete Freund’s adjuvant or conjugated to reduced mannan and responses were assessed. Results: Linear double-mutant peptide [L144, R147]PLP139-151 induced high levels of IL-4 responses and low levels of IgG total, and cyclization of this analog elicited low levels of IFN-γ. Moreover, linear [L144, R147]PLP139-151 conjugated to reduced mannan did not induce IFN-γ, whilst both linear agonist PLP139-151 and cyclic agonist cyclo(139-151)PLP139-151 induced IFN-γ-secreting T cells. Molecular dynamics simulations of linear and cyclic(139-151)PLP139-151 analogs indicated the difference in topology of the most important for biological activity amino acids. Conclusion: Cyclic double-mutant analog cyclo(139-151) [L144, R147]PLP139-151 has potential for further studies for the immunotherapy of multiple sclerosis.