Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis.
Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4(+) T-cell responses remains unclear. In the present study, CD4(+) T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4(+)CD62L(+) T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4(+)CD62L(+) T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the T(H)1 or T(H)2 lineage. Repressive histone methylation marks were also evident at promoter regions for the T(H)1 cytokine IFN-gamma and the T(H)2 transcription factor GATA-3 in naïve CD4(+) T cells from CLP mice. These results provide evidence that CD4(+) T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription.
Carson
William F
WF
Department of Pathology, University of Michigan, Ann Arbor, MI 48105, USA. wfcarson@umich.edu
Cavassani
Karen A
KA
Ito
Toshihiro
T
Schaller
Matthew
M
Ishii
Makoto
M
Dou
Yali
Y
Kunkel
Steven L
SL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured / Q000276:immunology; D042002:Chromatin Assembly and Disassembly / Q000276:immunology; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D006657:Histones / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics; D007416:Intestinal Perforation / Q000150:complications; D019041:L-Selectin / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms
C515371:Ccr7 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006657:Histones; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019041:L-Selectin; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4