title: Systemic inflammatory response elicited by superantigen destabilizes T regulatory cells, rendering them ineffective during toxic shock syndrome.
abstract: Life-threatening infections caused by Staphylococcus aureus, particularly the community-acquired methicillin-resistant strains of S. aureus, continue to pose serious problems. Greater virulence and increased pathogenicity of certain S. aureus strains are attributed to higher prevalence of exotoxins. Of these exotoxins, the superantigens (SAg) are likely most pathogenic because of their ability to rapidly and robustly activate the T cells even in extremely small quantities. Therefore, countering SAg-mediated T cell activation using T regulatory cells (Tregs) might be beneficial in diseases such as toxic shock syndrome (TSS). As the normal numbers of endogenous Tregs in a typical host are insufficient, we hypothesized that increasing the Treg numbers by administration of IL-2/anti-IL-2 Ab immune complexes (IL2C) or by adoptive transfer of ex vivo expanded Tregs might be more effective in countering SAg-mediated immune activation. HLA-DR3 transgenic mice that closely recapitulate human TSS were treated with IL2C to increase endogenous Tregs or received ex vivo expanded Tregs. Subsequently, they were challenged with SAg to induce TSS. Analyses of various parameters reflective of TSS (serum cytokine/chemokine levels, multiple organ pathology, and SAg-induced peripheral T cell expansion) indicated that increasing the Tregs failed to mitigate TSS. On the contrary, serum IFN-γ levels were increased in IL2C-treated mice. Exploration into the reasons behind the lack of protective effect of Tregs revealed IL-17 and IFN-γ-dependent loss of Tregs during TSS. In addition, significant upregulation of glucocorticoid-induced TNFR family-related receptor on conventional T cells during TSS could render them resistant to Treg-mediated suppression, contributing to failure of Treg-mediated immune regulation.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Ashenafi Y
authors.initials: AY
authors.lastname: Tilahun
authors.affiliation: Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Vaidehi R
authors.initials: VR
authors.lastname: Chowdhary
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905 rajagopalan.govindarajan@mayo.edu.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000494:pharmacology; D004768:Enterotoxins / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000096:biosynthesis; D005938:Glucocorticoids; D059805:HLA-DR alpha-Chains / Q000235:genetics / Q000276:immunology; D059806:HLA-DR beta-Chains / Q000235:genetics / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity; D051379:Mice; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D012772:Shock, Septic / Q000276:immunology* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation*; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D004768:Enterotoxins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D059805:HLA-DR alpha-Chains; D059806:HLA-DR beta-Chains; D015803:HLA-DR3 Antigen; D020381:Interleukin-17; D007376:Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D018089:Superantigens; C106544:Tnfrsf18 protein, mouse; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma
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