title: A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection.
abstract: Staphylococcus aureus can cause difficult-to-treat chronic infections. We recently reported that S. aureus chronic infection was associated with a profound inhibition of T cell responses. In this study, we investigated the mechanisms responsible for the suppression of T cell responses during chronic S. aureus infection. Using in vitro coculture systems, as well as in vivo adoptive transfer of CFSE-labeled OT-II cells, we demonstrated the presence of immunosuppressive mechanisms in splenocytes of S. aureus-infected mice that inhibited the response of OT-II cells to cognate antigenic stimulation. Immunosuppression was IL-10/TGF-β independent but required cell-cell proximity. Using DEREG and Foxp3(gfp) mice, we demonstrated that CD4(+)CD25(+)Foxp3(+) regulatory T cells contributed, but only to a minor degree, to bystander immunosuppression. Neither regulatory B cells nor tolerogenic dendritic cells contributed to immunosuppression. Instead, we found a significant expansion of granulocytic (CD11b(+)Ly6G(+)Ly6C(low)) and monocytic (CD11b(+)Ly6G(-)Ly6C(high)) myeloid-derived suppressor cells (MDSC) in chronically infected mice, which exerted a strong immunosuppressive effect on T cell responses. Splenocytes of S. aureus-infected mice lost most of their suppressive activity after the in vivo depletion of MDSC by treatment with gemcitabine. Furthermore, a robust negative correlation was observed between the degree of T cell inhibition and the number of MDSC. An increase in the numbers of MDSC in S. aureus-infected mice by adoptive transfer caused a significant exacerbation of infection. In summary, our results indicate that expansion of MDSC and, to a minor degree, of regulatory T cells in S. aureus-infected mice may create an immunosuppressive environment that sustains chronic infection.
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Christina
authors.initials: C
authors.lastname: Tebartz
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Sarah Anita
authors.initials: SA
authors.lastname: Horst
authors.affiliation: Institute of Infection Immunology, Twincore, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany;
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beineke
authors.affiliation: Institute of Medical Microbiology, University Hospital of 48149 Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Peters
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; eva.medina@helmholtz-hzi.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Medina
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D056747:Immunomodulation; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D010641:Phenotype; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines