Attrition of memory CD8 T cells during sepsis requires LFA-1.
CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69+CD25intCD62LHI) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44HIOT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis.
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Mara A
MA
Serbanescu
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Kimberly M
KM
Ramonell
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Annette
A
Hadley
Department of Infectious Diseases and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA; and.
Lindsay M
LM
Margoles
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Rohit
R
Mittal
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
John D
JD
Lyons
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Zhe
Z
Liang
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Craig M
CM
Coopersmith
Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Mandy L
ML
Ford
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA; kevin.w.mcconnell@emory.edu.
Kevin W
KW
McConnell
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D024201:Bystander Effect; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D016654:Genes, RAG-1; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D018805:Sepsis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology / Q000637:transplantation
D000911:Antibodies, Monoclonal; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1
TCR; bystander activation; cytokine; lymphocyte activation