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

Qiang Shan,Micaela G Fosdick,Xiang Li,Hai-Hui Xue,Patrick W McGonagill,Weiqun Peng,Vladimir P Badovinac,Mikaela M Tremblay,Jon CD Houtman,Thomas S Griffith,Isaac J Jensen

doi:10.7554/elife.70989

Abstract

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.

Highlights

Dysregulated systemic inflammatory responses define septic events and the associated cytokine storm, which is comprised of both pro- and anti-inflammatory cytokines(CDC, 2020; Singer et al, 2016)
Our data cumulatively demonstrate how sepsis-induced changes in the composition of the pre-existing memory CD8 T cells alters the functional capability of the memory CD8 T cell population as a whole, thereby altering the host response to infection. 418 DISCUSSION In the present study we demonstrate that sepsis leads to a lasting change in the composition of the memory CD8 T cell compartment in the sepsis survivors
Danahy et al previously demonstrated that TRM were not susceptible to sepsis-induced lymphopenia, due to their exclusion from the vasculature (Danahy et al, 2017)

Summary

26 ABSTRACT

The global health burden due to sepsis and the associated cytokine storm is substantial. Memory CD8 T cells provide rapid cytolysis and cytokine production following re[31] 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. 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. 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

INTRODUCTION

109 RESULTS

418 DISCUSSION

914 MATERIALS AND METHODS

916 Ethics statement