Insertion of an immunodominant T helper cell epitope within the Group A Streptococcus M protein promotes an IFN-γ-dependent shift from a non-protective to a protective immune response

• Published in: Frontiers in immunology Vol. 14; p. 1241485
• Main Authors: Emami, Shiva, Rojas Converso, Thiago, Persson, Jenny J., Johansson-Lindbom, Bengt
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 2023
• Subjects: Antibodies; B cells; Basic Medicine; group A Streptococcus; IFN-γ; IgG2c; Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi); Immunology; Immunology in the Medical Area (including Cell and Immunotherapy); Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; T cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1241485

The common pathogen Group A Streptococcus (GAS, Streptococcus pyogenes ) is an extracellular bacterium that is associated with a multitude of infectious syndromes spanning a wide range of severity. The surface-exposed M protein is a major GAS virulence factor that is also target for protective antibody responses. In this study, we use a murine immunization model to investigate aspects of the cellular and molecular foundation for protective adaptive immune responses generated against GAS. We show that a wild type M1 GAS strain induces a non-protective antibody response, while an isogenic strain carrying the immunodominant 2W T helper cell epitope within the M protein elicits an immune response that is protective against the parental non-recombinant M1 GAS strain. Although the two strains induce total anti-GAS IgG levels of similar magnitude, only the 2W-carrying strain promotes elevated titers of the complement-fixing IgG2c subclass. Protection is dependent on IFN-γ, and IFN-γ-deficient mice show a specific reduction in IgG2c levels. Our findings suggest that inclusion of the 2W T cell epitope in the M protein confers essential qualitative alterations in the adaptive immune response against GAS, and that sparsity in IFN-γ-promoting Th cell epitopes in the M protein may constitute an immune evasion mechanism, evolved to allow the pathogen to avoid attack by complement-fixing antibodies.