title: Injury primes the immune system for an enhanced and lethal T-cell response against bacterial superantigen.
abstract: We previously reported the high lethality of CD4+ T-cell activation in burn-injured T-cell receptor (TCR) transgenic mice. This suggested to us that T-cells may play a role in the development of the systemic inflammatory response syndrome (SIRS) which can occur after severe injury. In this study, we sought a more clinically relevant model to test the hypothesis that naturally produced bacterial toxins that are known to act as potent polyclonal T-cell activating agents may induce a similar lethal shock-like response in injured, non-TCR transgenic mice. Accordingly, sham- or burn-injured mice were treated with various doses of staphylococcal enterotoxin A (SEA), then observed for 48-hour mortality. We observed 94% and 56% 48-h mortality when burn-injured mice were given 15 microg and 10 microg of SEA, respectively, while neither SEA dose caused mortality in sham-injured mice. The assessment of serum cytokine levels demonstrated significantly elevated interleukin 2 (IL-2) and tumor necrosis factor alpha (TNFalpha) levels when compared to sham mice (P < 0.01). In vitro studies confirmed our in vivo results and also demonstrated elevated levels of interferon gamma (IFNgamma) (P < 0.01). We also observed a novel injury-dependent switch from CD4+ to CD8+ T-cells as the dominant T-cell type producing TNFalpha and IFNgamma in response to SEA stimulation in vitro. Taken together, our findings indicate that injury primes the immune system for an augmented early T-cell response that can result in a lethal shock-like syndrome.
authors.affiliation: Department of Surgery (Immunology), Harvard Medical School/Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Kell
authors.forename: E G
authors.initials: EG
authors.lastname: Kavanaugh
authors.forename: A
authors.initials: A
authors.lastname: Goebel
authors.forename: C C
authors.initials: CC
authors.lastname: Soberg
authors.forename: J A
authors.initials: JA
authors.lastname: Lederer
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002056:Burns / Q000276:immunology* / Q000382:microbiology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D004768:Enterotoxins; D007376:Interleukin-2; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma