Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells

eLife

Qiang Shan¹  Hai-Hui Xue¹  Isaac J Jensen²  Vladimir P Badovinac³  Xiang Li⁴  Weiqun Peng⁴  Patrick W McGonagill⁵  Micaela G Fosdick⁶  Mikaela M Tremblay⁶  Jon CD Houtman⁷  Thomas S Griffith⁸ 

[1] Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, United States;Department of Pathology, University of Iowa, Iowa City, United States;Department of Pathology, University of Iowa, Iowa City, United States;Interdisciplinary Graduate Program in Molecular Medicine, University of Iowa, Iowa City, United States;Department of Physics, The George Washington University, Washington, United States;Department of Surgery, University of Iowa, Iowa City, United States;Interdisciplinary Graduate Program in Molecular Medicine, University of Iowa, Iowa City, United States;Interdisciplinary Graduate Program in Molecular Medicine, University of Iowa, Iowa City, United States;Interdisciplinary Graduate Program in Molecular Medicine, University of Iowa, Iowa City, United States;Microbiology, Immunology, and Cancer Biology PhD Program, University of Minnesota, Minneapolis, United States;Department of Urology, University of Minnesota, Minneapolis, United States;Center for Immunology, University of Minnesota, Minneapolis, United States;Masonic Cancer Center, University of Minnesota, Minneapolis, United States;Minneapolis VA Health Care System, Minneapolis, United States;

关键词: CD8 T cell;    central memory;    homeostatic proliferation;    sepsis;    Human;    Mouse;   

DOI  :  10.7554/eLife.70989

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

【 授权许可】

CC BY