Elimination of an Immunodominant CD4+ T Cell Epitope in Human IFN-β Does Not Result in an In Vivo Response Directed at the Subdominant Epitope

Abstract

The BALB/cByJ mouse strain displays an immunodominant T cell response directed at the same CD4+ T cell epitope peptide region in human IFN-β, as detected in a human population-based assay. BALB/cByJ mice also recognize a second region of the protein with a lesser magnitude proliferative response. Critical residue testing of the immunodominant peptide showed that both BALB/cByJ mice and the human population response were dependent on an isoleucine residue at position 129. A variant IFN-β molecule was constructed containing the single amino acid modification, I129V, in the immunodominant epitope. The variant displayed 100% of control antiproliferation activity. Mice immunized with unmodified IFN-β responded weakly in vitro to the I129V variant. However, BALB/cByJ mice immunized with the I129V variant were unable to respond to either the I129V variant or the unmodified IFN-β molecule by either T cell proliferation or Ag-specific IgG1 Ab production. This demonstrates that a single amino acid change in an immunodominant epitope can eliminate an immune response to an otherwise intact therapeutic protein. The elimination of the immunodominant epitope response also eliminated the response to the subdominant epitope in the protein. Modifying functionally immunodominant T cell epitopes within proteins may obviate the need for additional subdominant epitope modifications.

Quality and Vaccine Efficacy of CD4+ T Cell Responses Directed to Dominant and Subdominant Epitopes in ESAT-6 from Mycobacterium tuberculosis

“…The explanation for this latter observation is not clear, but it was suggested that for some subdominant epitopes the efficient priming of responses depends on the establishment of a productive proliferative response to the immunodominant epitope (31).…”

“…2). No IFN-␥ release was found in response to the control peptide (ESAT-6 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] ). In addition to the immunodominant P1 (ESAT-6 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] ) epitope, the analysis of peptides covering the full sequence of ESAT-6 revealed two additional subdominant epitopes to which T cells are not primed during the natural infection.…”

Therapeutic enzyme deimmunization by combinatorial T-cell epitope removal using neutral drift

“…However, the identification and removal of B-cell epitopes is exceedingly difficult given their conformational nature, and is further complicated by our incomplete knowledge of naive antibody repertoires, and how they vary across different human populations. In contrast, there is extensive evidence from animal models, in vitro experiments, and early stage clinical studies, that the disruption of T-cell epitopes can reduce antibody responses in some therapeutic proteins (13,14). T-cell receptors on CD4þ T cells recognize antigenic peptides (typically 13-25mers) presented in complex with MHC-II molecules on the surface of antigen-presenting cells (APCs).…”

In Vitro Evaluation of Humanized/De-immunized Anti-PSMA Immunotoxins for the Treatment of Prostate Cancer

“…Therefore, many attempts have been made to diminish the immunogenicity of immunotoxins by humanization/de-immunization of the antibody binding domains (14,15), modification with macromolecules (16)(17)(18)(19), or structural changes of the PE domain (20)(21)(22). Several preclinical studies described that deletions or mutations within the PE toxin domain led to the removal of immunodominant Band T-cell epitopes and successfully contributed to diminished immunogenicity and reduced ADA production (20)(21)(22).…”