title: T-cell activation differentially mediates the host response to sepsis.
abstract: Survival during sepsis requires both swift control of infectious organisms and tight regulation of the associated inflammatory response. As the role of T cells in sepsis is somewhat controversial, we examined the impact of increasing antigen-dependent activation of CD4 T cells in a murine model of cecal ligation and puncture using T-cell receptor transgenic II (OT-II) mice that are specific for chicken ovalbumin (OVA) in the context of major histocompatibility complex II. Here, we injected OT-II mice with 0, 1, or 100 μg of OVA and demonstrate that increased antigen treatment resulted in increased numbers of activated splenic CD4 T cells. Vehicle-treated, septic OT-II mice had decreased survival, increased bacterial load, and increased levels of IL-6. Interestingly, this decrease in survival was abrogated when OT-II mice were injected with 1 μg OVA, which was correlated with normalized bacterial load and levels of IL-6. However, when OT-II mice were injected with 100 μg OVA, decreased survival was restored but, in contrast to vehicle-treated OT-II mice, had decreased bacterial load and enhanced IL-6 levels. We also observed that neutrophil oxidative burst and phagocytosis were dependent on CD4 T-cell activation. Further, at extreme levels of T-cell activation, intestinal permeability was significantly increased. Altogether, we conclude that too little CD4 T-cell activation produces dysfunctional neutrophils leading to decreased bacteria clearance and survival, whereas too much CD4 T-cell activation produces a neutrophil phenotype that leads to efficient bacterial clearance but with increased tissue damage and mortality.
authors.affiliation: Division of Research, Department of Surgery, University of Cincinnati College of Medicine, OH, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kasten
authors.forename: Johannes
authors.initials: J
authors.lastname: Tschöp
authors.forename: Holly S
authors.initials: HS
authors.lastname: Goetzman
authors.forename: Lisa G
authors.initials: LG
authors.lastname: England
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dattilo
authors.forename: Cindy M
authors.initials: CM
authors.lastname: Cave
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Seitz
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
authors.forename: Charles C
authors.initials: CC
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000502:physiology; D016897:Respiratory Burst / Q000502:physiology; D018805:Sepsis / Q000276:immunology*
chemical_list: D015850:Interleukin-6