CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis.

Kimberly M Ramonell,Ching-Wen Chen,John D Lyons,Nathan J Klingensmith,Annette Hadley,Mandy L Ford,Katherine T Fay,Kevin W Mcconnell,Craig M Coopersmith,Wenxiao Zhang,Shree Ram Singh

doi:10.1371/journal.pone.0188882

Abstract

Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.

Highlights

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection and is responsible for more than 300,000 deaths annually [1, 2]
In light of the decrease in PD-1 expressing CD4+ T cells observed in septic animals treated with plerixafor, we evaluated the effect of CXCR4 blockade on the expression of additional coinhibitory markers on CD4+ T cells, including LAG-3 and 2B4
In this series of investigations, we found that CXCR4 blockade improved survival in murine polymicrobial sepsis, increased the absolute number of circulating CD4+ and CD8+ T cells, and mitigated sepsis-induced T cell exhaustion phenotypes

Summary

Introduction

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection and is responsible for more than 300,000 deaths annually [1, 2]. With the exception of antibiotics, current therapy is limited to non-specific supportive care and mortality remains at 40% [3, 4]. There is increasing appreciation for the central role that immunologic dysfunction plays in driving sepsis mortality. CXCR4 blockade improves sepsis mortality analysis, decision to publish, or preparation of the manuscript

Methods

Results

Conclusion