title: Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function.
abstract: Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4(+)/CD8(+) T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells.
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Robby
authors.initials: R
authors.lastname: Markwart
authors.affiliation: Dept. of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Condotta
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Requardt
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Farina
authors.initials: F
authors.lastname: Borken
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Schubert
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Weigel
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Dept. for Anaesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota, United States of America; Center for Immunology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
authors.affiliation: Clinic of Internal Medicine I, Jena University Hospital, Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Förster
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Center for Clinical Studies, Jena University Hospital, Jena, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Brunkhorst
authors.affiliation: Dept. of Pathology, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
authors.affiliation: Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rubio
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007249:Inflammation / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell