T-cell activation differentially mediates the host response to sepsis.
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.
Kasten
Kevin R
KR
Division of Research, Department of Surgery, University of Cincinnati College of Medicine, OH, USA.
Tschöp
Johannes
J
Goetzman
Holly S
HS
England
Lisa G
LG
Dattilo
Jonathan R
JR
Cave
Cindy M
CM
Seitz
Aaron P
AP
Hildeman
David A
DA
Caldwell
Charles C
CC
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*
D015850:Interleukin-6