title: Robust antigen specific th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection.
abstract: Group A streptococcus (GAS, Streptococcus pyogenes) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to quantify pMHCII-specific CD4+ helper T cells and evaluate their contribution to both protective immunity and autoimmune complications induced by specific bacterial pathogens. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4+ helper T cell response in C57BL/6 mice that express the I-A(b) MHCII molecule. Following intranasal inoculation with GAS-2W, antigen-experienced 2W:I-A(b)-specific CD4+ T cells were identified in the nasal-associated lymphoid tissue (NALT) that produced IL-17A or IL-17A and IFN-γ if infection was recurrent. The dominant Th17 response was also dependent on the intranasal route of inoculation; intravenous or subcutaneous inoculations produced primarily IFN-γ+ 2W:I-A(b+) CD4+ T cells. The acquisition of IL-17A production by 2W:I-A(b)-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-γ-producing 2W:I-A(b)-specific CD4+ T cells. Our results suggest that an imbalance between IL-17- and IFN-γ-producing CD4+ T cells could contribute to GAS carriage in humans.
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America. dile0003@umn.edu
authors.forename: Thamotharampillai
authors.initials: T
authors.lastname: Dileepan
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Linehan
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Cleary
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000172:deficiency / Q000276:immunology*; D008221:Lymphoid Tissue / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D020381:Interleukin-17; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; C014689:streptococcal M protein; D007371:Interferon-gamma