CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis
| Autor: | Mandy L. Ford, John D. Lyons, Wenxiao Zhang, Annette Hadley, Kimberly M. Ramonell, Kevin W. McConnell, Nathan J. Klingensmith, Craig M. Coopersmith, Ching-Wen Chen, Katherine T. Fay |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Male Physiology lcsh:Medicine CD8-Positive T-Lymphocytes Pathology and Laboratory Medicine CXCR4 Memory T cells Immunological synapse White Blood Cells Mice 0302 clinical medicine Animal Cells Immune Physiology Medicine and Health Sciences Cytotoxic T cell lcsh:Science Innate Immune System Multidisciplinary T Cells Animal Models Flow Cytometry 3. Good health medicine.anatomical_structure Experimental Organism Systems Cytokines Female Cellular Types Research Article Receptors CXCR4 T cell Immune Cells Immunology Cytotoxic T cells Mouse Models Bone Marrow Cells Research and Analysis Methods Sepsis 03 medical and health sciences Immune system Signs and Symptoms Model Organisms Diagnostic Medicine medicine Animals Blood Cells business.industry lcsh:R Biology and Life Sciences Cell Biology Molecular Development medicine.disease Survival Analysis Mice Inbred C57BL Disease Models Animal 030104 developmental biology Immune System lcsh:Q Bone marrow business Immunologic Memory CD8 030215 immunology Developmental Biology |
| Zdroj: | PLoS ONE, Vol 12, Iss 12, p e0188882 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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 naive 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. |
| Databáze: | OpenAIRE |
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