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

• Type of Material: Article
• Authors: Kimberly M. Ramonell, Emory University; Wenxiao Zhang, Emory University; Annette Hadley, Emory University; Ching-wen Chen, Emory University; Katherine T. Fay, Emory University; John D. Lyons, Emory University; Nathan J. Klingensmith, Emory University; Kevin McConnell, Emory University; Craig Coopersmith, Emory University; Mandy L Ford, Emory University
• Language: English
• Date: 2017-12-12
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Ramonell et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0188882
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 12
• Issue: 12
• Start Page: e0188882
• End Page: e0188882
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health grants GM104323, GM109779, and GM113228 (to MLF and CMC), GM072808 and GM095442 (to CMC), GM117895 (to JDL), GM110537 (to KWM) and Shock Society Research Fellowship for Early Career Investigators (to KWM).
• Keywords: Cytotoxic T cells; MORTALITY; BETA-SELECTION; Cytokines; BONE-MARROW; Bone marrow cells; Memory T cells; Multidisciplinary Sciences; Science & Technology; Mouse models; EXPRESSION; PD-1; Science & Technology - Other Topics; IMMUNOSUPPRESSION; SEPTIC SHOCK; Sepsis; Immune cells; MICE; AMD3100; IMMUNOTHERAPY; T cells
• Research Categories: Biology, Cell; Health Sciences, Oncology; Health Sciences, Medicine and Surgery

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.