Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis

Chao Cao, Muming Yu, Yanfen Chai, Chao Cao, Muming Yu, Yanfen Chai

Abstract

Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection that leads to uncontrolled inflammatory response followed by immunosuppression. However, despite the high mortality rate, no specific treatment modality or drugs with high efficacy is available for sepsis to date. Although improved treatment strategies have increased the survival rate during the initial state of excessive inflammatory response, recent trends in sepsis show that mortality occurs at a period of continuous immunosuppressive state in which patients succumb to secondary infections within a few weeks or months due to post-sepsis "immune paralysis." Immune cell alteration induced by uncontrolled apoptosis has been considered a major cause of significant immunosuppression. Particularly, apoptosis of lymphocytes, including innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcomes. Multiple postmortem studies have confirmed that sepsis-induced immune cell apoptosis occurs in all age groups, including neonates, pediatric, and adult patients, and it is considered to be a primary contributing factor to the immunosuppressive pathophysiology of sepsis. Therapeutic perspectives targeting apoptosis through various strategies could improve survival in sepsis. In this review article, we will focus on describing the major apoptosis process of immune cells with respect to physiologic and molecular mechanisms. Further, advances in apoptosis-targeted treatment modalities for sepsis will also be discussed.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. Immune response in sepsis.
Fig. 1. Immune response in sepsis.
Early activation of both innate and adaptive immune response is involved in the pathogenesis of sepsis. The peak mortality rates during the early period (top red line) were due to overwhelming inflammatory response, also known as “cytokine storm,” which comprises fever, refractory shock, inadequate resuscitation, and cardiac or pulmonary failure. Meanwhile, mortality at the later period is due to persistent immunosuppression with secondary infections that results in organ injury and/or failure. Although more sophisticated ICU care has improved mortality, patients still die at the later period or after several years owing to the persistent immunosuppression, immune dysfunction, or chronic catabolism
Fig. 2. Alterations in innate and adaptive…
Fig. 2. Alterations in innate and adaptive immunity in the pathophysiology of sepsis.
Early activation of innate immunity is the first line of defense against infection and plays a central role in the initiation of adaptive immunity. However, in sepsis, excessive immune responses lead to several alterations in innate and adaptive immunity that contribute to protracted immunosuppression and increase the risk for opportunistic infection. In some way, sepsis can be considered as a race to the death between host immune response and pathogens that seek an advantage by impairing the host immune defenses
Fig. 3. Sepsis alters innate and adaptive…
Fig. 3. Sepsis alters innate and adaptive immune cells.
Sepsis-induced immune paralysis is characterized by immunological defects that impair host immunity. Lymphoid cell loss, often resulting in the diminished capacity to fight and eliminate pathogens, is a primary feature of immune suppression during sepsis. Altered immune cell function induced by uncontrolled apoptosis is a major cause of profound immunosuppression. Lymphocyte apoptosis, including that of innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcome in various diseases. As shown here, sepsis rapidly triggers profound apoptosis in macrophages/monocytes, dendritic cells, NK cells, γδ T cells, CD4+ T cells, and B cells. However, apoptosis of neutrophils is delayed, and Treg cells are more resistant to sepsis-induced apoptosis. Immune cell depletion due to apoptosis is the primary mechanism of sepsis-induced immune suppression
Fig. 4. Sepsis-induced delayed apoptosis and recruitment…
Fig. 4. Sepsis-induced delayed apoptosis and recruitment of neutrophils into tissues lead to multiple organ dysfunction syndrome.
The apoptosis of neutrophils is delayed during the first 24 h after the initiation of sepsis. Then neutrophils are recruited and infiltrate into tissues, aggravating the ongoing neutrophil dysfunction with persistent immune dysfunction and inflammation persistence. Neutrophil infiltration in the lungs is a pathological hallmark of sepsis-induced acute lung injury or acute respiratory distress syndrome as well as of organ dysfunction in the liver and heart. Representative histological changes in tissues are shown in hematoxylin and eosin-stained samples (original magnification ×400). Arrows denote the recruitment and infiltration of neutrophils into tissues

References

    1. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect. Dis. 2013;13:260–268. doi: 10.1016/S1473-3099(13)70001-X.
    1. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol. Med. 2014;20:195–203. doi: 10.1016/j.molmed.2014.01.007.
    1. Fink MP, Warren HS. Strategies to improve drug development for sepsis. Nat. Rev. Drug Discov. 2014;13:741–758. doi: 10.1038/nrd4368.
    1. Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304–377. doi: 10.1007/s00134-017-4683-6.
    1. Marik PE, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43:625–632. doi: 10.1007/s00134-016-4675-y.
    1. Dellinger RP, Vincent JL. The Surviving Sepsis Campaign sepsis change bundles and clinical practice. Crit. Care. 2005;9:653–654. doi: 10.1186/cc3952.
    1. Suarez De La Rica A, Gilsanz F, Maseda E. Epidemiologic trends of sepsis in western countries. Ann. Transl. Med. 2016;4:325. doi: 10.21037/atm.2016.08.59.
    1. Cohen J, et al. Sepsis: a roadmap for future research. Lancet Infect. Dis. 2015;15:581–614. doi: 10.1016/S1473-3099(15)70112-X.
    1. Fleischmann C, et al. Assessment of global incidence and mortality of hospital-treated sepsis. current estimates and limitations. Am. J. Respir. Crit. Care Med. 2016;193:259–272. doi: 10.1164/rccm.201504-0781OC.
    1. van der Poll T, et al. The immunopathology of sepsis and potential therapeutic targets. Nat. Rev. Immunol. 2017;17:407–420. doi: 10.1038/nri.2017.36.
    1. Langley RJ, et al. An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci. Transl. Med. 2017;5:195ra195.
    1. Hall MJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011;62:1–8.
    1. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 2013;13:862–874. doi: 10.1038/nri3552.
    1. Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J. Clin. Invest. 2016;126:23–31. doi: 10.1172/JCI82224.
    1. Needham DM, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference. Crit. Care Med. 2012;40:502–529. doi: 10.1097/CCM.0b013e318232da75.
    1. Kaukonen KM, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N. Engl. J. Med. 2015;372:1629–1638. doi: 10.1056/NEJMoa1415236.
    1. Vincent J-L, et al. Sepsis definitions: time for change. Lancet. 2013;381:774–775. doi: 10.1016/S0140-6736(12)61815-7.
    1. Singer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315:801–810. doi: 10.1001/jama.2016.0287.
    1. Kahn JM, et al. The epidemiology of chronic critical illness in the United States. Crit. Care Med. 2015;43:282–287. doi: 10.1097/CCM.0000000000000710.
    1. Hotchkiss RS, Opal S. Immunotherapy for sepsis–a new approach against an ancient foe. N. Engl. J. Med. 2010;363:87–89. doi: 10.1056/NEJMcibr1004371.
    1. Torgersen C, et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth. Analg. 2009;108:1841–1847. doi: 10.1213/ane.0b013e318195e11d.
    1. Otto GP, et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit. Care. 2011;15:R183. doi: 10.1186/cc10332.
    1. Boomer JS, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–2605. doi: 10.1001/jama.2011.1829.
    1. Hotchkiss RS, et al. Sepsis and septic shock. Nat. Rev. Dis. Prim. 2016;2:16045. doi: 10.1038/nrdp.2016.45.
    1. Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nat. Rev. Immunol. 2006;6:813–822. doi: 10.1038/nri1943.
    1. Hotchkiss RS, Tinsley KW, Karl IE. Role of apoptotic cell death in sepsis. Scand. J. Infect. Dis. 2009;35:585–592. doi: 10.1080/00365540310015692.
    1. Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol. Rev. 2016;274:30–353. doi: 10.1111/imr.12499.
    1. Hattori Y, et al. Insights into sepsis therapeutic design based on the apoptotic death pathway. J. Pharmacol. Sci. 2010;14:354–365. doi: 10.1254/jphs.10R04CR.
    1. Hotchkiss RS, Crouser E. Imaging apoptosis in sepsis–a technology we would die for! Crit. Care Med. 2015;43:2506–2508. doi: 10.1097/CCM.0000000000001289.
    1. Oberholzer, C. et al. Targeted adenovirus-induced expression of IL-10 decreases thymic apoptosis and improves survival in murine sepsis. Proc. Natl Acad. Sci. USA98,11503–11508 (2001).
    1. Ayala A, et al. Blockade of apoptosis as a rational therapeutic strategy for the treatment of sepsis. Novartis Found. Symp . 2007;280:37–49.
    1. Cohen JJ, et al. Apoptosis and programmed cell death in immunity. Annu. Rev. Immunol. 1992;10:267–293. doi: 10.1146/annurev.iy.10.040192.001411.
    1. Ayala A, et al. Apoptosis in sepsis: mechanisms, clinical impact and potential therapeutic targets. Curr. Pharm. Des. 2009;14:1853–1859. doi: 10.2174/138161208784980617.
    1. Hotchkiss RS, et al. Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock. Crit. Care Med. 2000;28:3207–3217. doi: 10.1097/00003246-200009000-00016.
    1. Zheng D, et al. Inhibition of microRNA 195 prevents apoptosis and multiple-organ injury in mouse models of sepsis. J. Infect. Dis. 2016;213:1661–1670. doi: 10.1093/infdis/jiv760.
    1. Benjamim CF, et al. Reversal of long-term sepsis-induced immunosuppression by dendritic cells. Blood. 2005;105:3588–3595. doi: 10.1182/blood-2004-08-3251.
    1. Zeerleder S, et al. Elevated nucleosome levels in systemic inflammation and sepsis. Crit. Care Med. 2003;31:1947–1951. doi: 10.1097/01.CCM.0000074719.40109.95.
    1. Hotchkiss RS, et al. Cell death. N. Engl. J. Med. 2009;361:1570–1583. doi: 10.1056/NEJMra0901217.
    1. Huber-Lang MS, et al. Complement-induced impairment of innate immunity during sepsis. J. Immunol. 2002;169:3223–31. doi: 10.4049/jimmunol.169.6.3223.
    1. Chiche L, et al. Interferon-gamma production by natural killer cells and cytomegalovirus in critically ill patients. Crit. Care Med. 2012;40:3162–3169. doi: 10.1097/CCM.0b013e318260c90e.
    1. Henson PM, Bratton DL. Antiinflammatory effects of apoptotic cells. J. Clin. Invest. 2013;123:2773–2774. doi: 10.1172/JCI69344.
    1. Lerman YV, et al. Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin alpha3beta1-dependent. Blood. 2011;124:3515–3523. doi: 10.1182/blood-2014-01-552943.
    1. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 2006;6:173–182. doi: 10.1038/nri1785.
    1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 2013;13:159–175. doi: 10.1038/nri3399.
    1. Summers C, et al. Neutrophil kinetics in health and disease. Trends Immunol. 2010;31:318–324. doi: 10.1016/j.it.2010.05.006.
    1. Tamayo E, et al. Evolution of neutrophil apoptosis in septic shock survivors and nonsurvivors. J. Crit. Care. 2012;27:415 e1–11. doi: 10.1016/j.jcrc.2011.09.001.
    1. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33:657–670. doi: 10.1016/j.immuni.2010.11.011.
    1. Davey MS, et al. Microbe-specific unconventional T cells induce human neutrophil differentiation into antigen cross-presenting cells. J. Immunol. 2014;193:3704–3716. doi: 10.4049/jimmunol.1401018.
    1. Geering B, Simon HU. Peculiarities of cell death mechanisms in neutrophils. Cell Death Differ. 2011;18:1457–1469. doi: 10.1038/cdd.2011.75.
    1. Taneja R, et al. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit. Care Med. 2004;32:1460–1469. doi: 10.1097/01.CCM.0000129975.26905.77.
    1. Delano MJ, et al. Sepsis induces early alterations in innate immunity that impact mortality to secondary infection. J. Immunol. 2013;186:195–202. doi: 10.4049/jimmunol.1002104.
    1. Eash KJ, et al. CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J. Clin. Invest. 2010;120:2423–2431. doi: 10.1172/JCI41649.
    1. Delano MJ, et al. Neutrophil mobilization from the bone marrow during polymicrobial sepsis is dependent on CXCL12 signaling. J. Immunol. 2011;187:911–918. doi: 10.4049/jimmunol.1100588.
    1. Grailer JJ, et al. Persistent neutrophil dysfunction and suppression of acute lung injury in mice following cecal ligation and puncture sepsis. J. Innate Immun. 2014;6:695–705. doi: 10.1159/000362554.
    1. Abraham E. Neutrophils and acute lung injury. Crit. Care Med. 2003;31(4 Suppl):S195–199. doi: 10.1097/01.CCM.0000057843.47705.E8.
    1. Grommes J, Soehnlein O. Contribution of neutrophils to acute lung injury. Mol. Med. 2011;17:293–307. doi: 10.2119/molmed.2010.00138.
    1. Leitch AE, et al. Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation. Cell Death Differ. 2012;19:1950–1961. doi: 10.1038/cdd.2012.80.
    1. Lucas CD, et al. Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung. Mucosal Immunol. 2014;7:857–868. doi: 10.1038/mi.2013.102.
    1. de Kleijn S, et al. Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia. PLoS ONE. 2012;7:e38255. doi: 10.1371/journal.pone.0038255.
    1. Fialkow L, et al. Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome. Crit. Care. 2006;10:R155. doi: 10.1186/cc5090.
    1. Anne Morrison C, et al. Increased apoptosis of peripheral blood neutrophils is associated with reduced incidence of infection in trauma patients with hemorrhagic shock. J. Infect. 2013;66:87–94. doi: 10.1016/j.jinf.2012.10.001.
    1. Jia SH, Parodo J, et al. Activated neutrophils induce epithelial cell apoptosis through oxidant-dependent tyrosine dephosphorylation of caspase-8. Am. J. Pathol. 2014;184:1030–1040. doi: 10.1016/j.ajpath.2013.12.031.
    1. Patera AC, et al. Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1. J. Leukoc. Biol. 2016;100:1239–1254. doi: 10.1189/jlb.4HI0616-255R.
    1. Morris AC, et al. C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients. Blood. 2011;117:5178–5188. doi: 10.1182/blood-2010-08-304667.
    1. Robertson CM, et al. Neutrophil depletion causes a fatal defect in murine pulmonary Staphylococcus aureus clearance. J. Surg. Res. 2008;150:278–285. doi: 10.1016/j.jss.2008.02.009.
    1. Drewry AM, et al. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42:383–391. doi: 10.1097/SHK.0000000000000234.
    1. Kasten KR, Muenzer JT, Caldwell CC. Neutrophils are significant producers of IL-10 during sepsis. Biochem. Biophys. Res. Commun. 2010;393:28–31. doi: 10.1016/j.bbrc.2010.01.066.
    1. Liu L, Sun B. Neutrophil pyroptosis: new perspectives on sepsis. Cell Mol. Life Sci. 2019;76:2031–2042. doi: 10.1007/s00018-019-03060-1.
    1. von Gunten S, et al. Different patterns of Siglec-9-mediated neutrophil death responses in septic. Shock. 2009;32:386–392. doi: 10.1097/SHK.0b013e3181a1bc98.
    1. Seok Y, et al. Delta neutrophil index: a promising diagnostic and prognostic marker for sepsis. Shock. 2012;37:242–246. doi: 10.1097/SHK.0b013e3182454acf.
    1. Parihar A, Eubank TD, Doseff AI. Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J. Innate Immun. 2010;2:204–215. doi: 10.1159/000296507.
    1. Lauvau G, Loke P, Hohl TM. Monocyte-mediated defense against bacteria, fungi, and parasites. Semin. Immunol. 2015;27:397–409. doi: 10.1016/j.smim.2016.03.014.
    1. Hamidzadeh K, et al. Macrophages and the recovery from acute and chronic inflammation. Annu. Rev. Physiol. 2017;79:567–592. doi: 10.1146/annurev-physiol-022516-034348.
    1. Molgaard-Nielsen D, Pasternak B, Hviid A. Oral fluconazole during pregnancy and risk of birth defects. N. Engl. J. Med. 2013;369:2061–2062. doi: 10.1056/NEJMoa1301066.
    1. Wang TS, Deng JC. Molecular and cellular aspects of sepsis-induced immunosuppression. J. Mol. Med. (Berl.) 2008;86:495–506. doi: 10.1007/s00109-007-0300-4.
    1. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–487. doi: 10.1016/j.it.2009.07.009.
    1. Fumeaux T, Pugin J. Is the measurement of monocytes HLA-DR expression useful in patients with sepsis? Intensive Care Med. 2008;32:1106–1108. doi: 10.1007/s00134-006-0205-7.
    1. Sinistro A, et al. Downregulation of CD40 ligand response in monocytes from sepsis patients. Clin. Vaccin. Immunol. 2008;15:1851–1858. doi: 10.1128/CVI.00184-08.
    1. Drewry AM, et al. Monocyte function and clinical outcomes in febrile and afebrile patients with severe sepsis. Shock. 2018;50:381–387. doi: 10.1097/SHK.0000000000001083.
    1. Lukaszewicz AC, et al. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit. Care Med. 2009;37:2746–2752.
    1. Monneret G, et al. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol. Med. 2008;14:64–78. doi: 10.2119/2007-00102.Monneret.
    1. Venet F, et al. Human CD4+CD25+ regulatory t lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J. Immunol. 2006;177:6540–6547. doi: 10.4049/jimmunol.177.9.6540.
    1. Schefold JC. Measurement of monocytic HLA-DR (mHLA-DR) expression in patients with severe sepsis and septic shock: assessment of immune organ failure. Intensive Care Med. 2010;36:1810–1812. doi: 10.1007/s00134-010-1965-7.
    1. Drewry AM, et al. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit. Care. 2016;20:334. doi: 10.1186/s13054-016-1505-0.
    1. Wu JF, et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit. Care. 2011;15:R220. doi: 10.1186/cc10457.
    1. Cazalis MA, et al. Decreased HLA-DR antigen-associated invariant chain (CD74) mRNA expression predicts mortality after septic shock. Crit. Care. 2013;17:R287. doi: 10.1186/cc13150.
    1. Andonegui G, et al. Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment. JCI Insight. 2018;3:99364. doi: 10.1172/jci.insight.99364.
    1. Hamers L, Kox M, Pickkers P. Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiol. 2015;81:426–439.
    1. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32:593–604. doi: 10.1016/j.immuni.2010.05.007.
    1. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 2012;122:787–795. doi: 10.1172/JCI59643.
    1. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J. Immunol. 2008;181:3733–3739. doi: 10.4049/jimmunol.181.6.3733.
    1. Peck-Palmer OM, et al. Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages. Shock. 2009;31:359–366. doi: 10.1097/SHK.0b013e31818ba2a2.
    1. Reizis B. Classical dendritic cells as a unique immune cell lineage. J. Exp. Med. 2012;209:1053–1056. doi: 10.1084/jem.20121038.
    1. Baratin M, et al. Homeostatic NF-kappaB signaling in steady-state migratory dendritic cells regulates immune homeostasis and tolerance. Immunity. 2015;42:627–639. doi: 10.1016/j.immuni.2015.03.003.
    1. Niessen F, et al. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature. 2008;452:452654–452658. doi: 10.1038/nature06663.
    1. Poehlmann H, et al. Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit. Care. 2009;13:R119. doi: 10.1186/cc7969.
    1. Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014;40:642–656. doi: 10.1016/j.immuni.2014.04.016.
    1. Pietruczuk M, et al. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis. World J. Gastroenterol. 2006;12:5344–5351. doi: 10.3748/wjg.v12.i33.5344.
    1. Grimaldi D, et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med. 2011;37:1438–1446. doi: 10.1007/s00134-011-2306-1.
    1. Kumar V. Dendritic cells in sepsis: potential immunoregulatory cells with therapeutic potential. Mol. Immunol. 2018;101:615–626. doi: 10.1016/j.molimm.2018.07.007.
    1. Guisset O, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med. 2007;33:148–152. doi: 10.1007/s00134-006-0436-7.
    1. Strother RK, et al. Polymicrobial sepsis diminishes dendritic cell numbers and function directly contributing to impaired primary CD8 T cell responses in vivo. J. Immunol. 2016;197:4301–4311. doi: 10.4049/jimmunol.1601463.
    1. Pene F, et al. Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect. Immun. 2009;77:5651–5658. doi: 10.1128/IAI.00238-09.
    1. Elsayh KI, et al. Dendritic cells in childhood sepsis. J. Crit. Care. 2013;28:881 e7–13. doi: 10.1016/j.jcrc.2013.05.007.
    1. Fan X, et al. Alterations of dendritic cells in sepsis: featured role in immunoparalysis. Biomed. Res. Int. 2015;2015:903720.
    1. Pastille E, et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J. Immunol. 2011;186:977–986. doi: 10.4049/jimmunol.1001147.
    1. Faivre V, et al. Human monocytes differentiate into dendritic cells subsets that induce anergic and regulatory T cells in sepsis. PLoS ONE. 2012;7:e47209. doi: 10.1371/journal.pone.0047209.
    1. Wu DD, Li T, Ji XY. Dendritic cells in sepsis: pathological alterations and therapeutic implications. J. Immunol. Res. 2017;2017:3591248.
    1. Weber GF, et al. Analysis of circulating plasmacytoid dendritic cells during the course of sepsis. Surgery. 2015;158:248–254. doi: 10.1016/j.surg.2015.03.013.
    1. Luan YY, et al. Insights into the apoptotic death of immune cells in sepsis. J. Interferon Cytokine Res. 2015;35:17–22. doi: 10.1089/jir.2014.0069.
    1. Scumpia PO, et al. CD11c+ dendritic cells are required for survival in murine polymicrobial sepsis. J. Immunol. 2005;175:3282–3286. doi: 10.4049/jimmunol.175.5.3282.
    1. Bohannon J, et al. Dendritic cell modification of neutrophil responses to infection after burn injury. J. Immunol. 2010;185:2847–2853. doi: 10.4049/jimmunol.0903619.
    1. Gautier EL, et al. Enhanced dendritic cell survival attenuates lipopolysaccharide-induced immunosuppression and increases resistance to lethal endotoxic shock. J. Immunol. 2008;180:6941–6946. doi: 10.4049/jimmunol.180.10.6941.
    1. Chiche L, et al. The role of natural killer cells in sepsis. J. Biomed. Biotechnol. 2011;2011:986491. doi: 10.1155/2011/986491.
    1. Bohannon J, Guo Y, Sherwood ER. The role of natural killer cells in the pathogenesis of sepsis: the ongoing enigma. Crit. Care. 2012;16:185. doi: 10.1186/cc11881.
    1. Vivier E, et al. Functions of natural killer cells. Nat. Immunol. 2008;9:503–510. doi: 10.1038/ni1582.
    1. Poli A, et al. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009;126:458–465. doi: 10.1111/j.1365-2567.2008.03027.x.
    1. Vivier E, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–49. doi: 10.1126/science.1198687.
    1. Stevenson MM, Riley EM. Innate immunity to malaria. Nat. Rev. Immunol. 2004;4:169–180. doi: 10.1038/nri1311.
    1. Bjorkstrom NK, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J. Exp. Med. 2011;208:13–21. doi: 10.1084/jem.20100762.
    1. Arase H, et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science. 2002;296:1323–1326. doi: 10.1126/science.1070884.
    1. Giamarellos-Bourboulis EJ. Natural killer cells in sepsis: detrimental role for final outcome. Crit. Care Med. 2014;42:1579–1580. doi: 10.1097/CCM.0000000000000352.
    1. Guo Y, et al. The biology of natural killer cells during sepsis. Immunology. 2018;153:190–202. doi: 10.1111/imm.12854.
    1. Forel JM, et al. Phenotype and functions of natural killer cells in critically-ill septic patients. PLoS ONE. 2012;7:e50446. doi: 10.1371/journal.pone.0050446.
    1. Venet F, et al. Early assessment of leukocyte alterations at diagnosis of septic shock. Shock. 2010;34:358–363. doi: 10.1097/SHK.0b013e3181dc0977.
    1. Holub M, et al. Lymphocyte subset numbers depend on the bacterial origin of sepsis. Clin. Microbiol. Infect. 2003;9:202–211. doi: 10.1046/j.1469-0691.2003.00518.x.
    1. Souza-Fonseca-Guimaraes F, et al. Toll-like receptors expression and interferon-gamma production by NK cells in human sepsis. Crit. Care. 2012;16:R206. doi: 10.1186/cc11838.
    1. Halstead ES, et al. Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients. Pediatr. Res. 2013;74:427–432. doi: 10.1038/pr.2013.121.
    1. Wesselkamper SC, et al. NKG2D is critical for NK cell activation in host defense against Pseudomonas aeruginosa respiratory infection. J. Immunol. 2008;181:5481–5489. doi: 10.4049/jimmunol.181.8.5481.
    1. Inoue S, et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J. Immunol. 2010;184:1401–1419. doi: 10.4049/jimmunol.0902307.
    1. Limaye AP, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300:413–422. doi: 10.1001/jama.2008.697.
    1. Hsu J, et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 2018;128:4654–4668. doi: 10.1172/JCI99317.
    1. Patil NK, et al. Targeting immune cell checkpoints during sepsis. Int. J. Mol. Sci. 2017;18:E2413. doi: 10.3390/ijms18112413.
    1. Kumar V. Natural killer cells in sepsis: underprivileged innate immune cells. Eur. J. Cell Biol. 2019;98:81–93. doi: 10.1016/j.ejcb.2018.12.003.
    1. Taniguchi T, et al. Malaria protection in beta 2-microglobulin-deficient mice lacking major histocompatibility complex class I antigens: essential role of innate immunity, including gammadelta T cells. Immunology. 2007;122:514–521. doi: 10.1111/j.1365-2567.2007.02661.x.
    1. Zheng J, et al. γδ-T cells: an unpolished sword in human anti-infection immunity. Cell Mol. Immunol. 2013;10:50–57. doi: 10.1038/cmi.2012.43.
    1. Heffernan DS, et al. A divergent response of innate regulatory T-cells to sepsis in humans: circulating invariant natural killer T-cells are preserved. Hum. Immunol. 2014;75:277–282. doi: 10.1016/j.humimm.2013.11.004.
    1. Andreu-Ballester JC, et al. Association of gammadelta T cells with disease severity and mortality in septic patients. Clin. Vaccin. Immunol. 2013;20:738–746. doi: 10.1128/CVI.00752-12.
    1. Douglas JJ, Tsang JL, Walley KR. Sepsis and the innate-like response. Intensive Care Med. 2014;40:249–251. doi: 10.1007/s00134-013-3141-3.
    1. Tschop J, et al. Gammadelta T cells mitigate the organ injury and mortality of sepsis. J. Leukoc. Biol. 2017;83:581–588. doi: 10.1189/jlb.0707507.
    1. Heffernan DS, et al. Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function. Shock. 2013;40:122–128. doi: 10.1097/SHK.0b013e31829ca519.
    1. Liao XL, et al. Phenotypic changes and impaired function of peripheral gammadelta T cells in patients with sepsis. Shock. 2017;48:321–328. doi: 10.1097/SHK.0000000000000857.
    1. Chung CS, et al. Deficiency of gammadelta T lymphocytes contributes to mortality and immunosuppression in sepsis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006;291:R1338–1343. doi: 10.1152/ajpregu.00283.2006.
    1. Wang L, et al. Antibacterial effect of human V gamma 2V delta 2 T cells in vivo. J. Clin. Invest. 2001;108:1349–1357. doi: 10.1172/JCI200113584.
    1. Hu YM, et al. Glutamine administration modulates lung gammadelta T lymphocyte expression in mice with polymicrobial sepsis. Shock. 2014;41:115–122. doi: 10.1097/SHK.0000000000000086.
    1. Pepper M, Jenkins MK. Origins of CD4+ effector and central memory T cells. Nat. Immunol. 2011;12:467–471. doi: 10.1038/ni.2038.
    1. Jensen IJ, et al. Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity. J. Immunol. 2018;200:1543–1553.
    1. Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 2007;117:1119–1127. doi: 10.1172/JCI31720.
    1. Kasten KR, et al. T-cell activation differentially mediates the host response to sepsis. Shock. 2010;34:377–383. doi: 10.1097/SHK.0b013e3181dc0845.
    1. Gouel-Cheron A, et al. CD4+ T-lymphocyte alterations in trauma patients. Crit. Care. 2012;16:432. doi: 10.1186/cc11376.
    1. Inoue S, et al. Reduction of immunocompetent T cells followed by prolonged lymphopenia in severe sepsis in the elderly. Crit. Care Med. 2013;41:810–819. doi: 10.1097/CCM.0b013e318274645f.
    1. Heffernan DS, et al. Failure to normalize lymphopenia following trauma is associated with increased mortality, independent of the leukocytosis pattern. Crit. Care. 2012;16:R12. doi: 10.1186/cc11157.
    1. Shindo Y, et al. Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression. Shock. 2015;43:334–343. doi: 10.1097/SHK.0000000000000317.
    1. Widera A. Physics. A walk across a quantum lattice. Science. 2015;347:1200–1201. doi: 10.1126/science.aaa6885.
    1. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat. Rev. Immunol. 2011;11:330–342. doi: 10.1038/nri2970.
    1. Unsinger J, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J. Immunol. 2010;184:3768–3779. doi: 10.4049/jimmunol.0903151.
    1. Singh A, et al. Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon gamma-producing T cells from apoptosis in patients with pulmonary tuberculosis. J. Infect. Dis. 2013;208:603–615. doi: 10.1093/infdis/jit206.
    1. Crouser ED, Hotchkiss RS. Desperate times call for desperate measures: self-cannibalism is protective during sepsis. Crit. Care Med. 2017;45:145–147. doi: 10.1097/CCM.0000000000002106.
    1. Ono S, et al. Mechanisms of sepsis-induced immunosuppression and immunological modification therapies for sepsis. Ann. Gastroenterol. Surg. 2018;2:351–358. doi: 10.1002/ags3.12194.
    1. Inoue S, et al. Persistent inflammation and T cell exhaustion in severe sepsis in the elderly. Crit. Care. 2014;18:R130. doi: 10.1186/cc13941.
    1. Guignant C, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit. Care. 2011;15:R99. doi: 10.1186/cc10112.
    1. Huang, X. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA106, 6303–6308 (2009).
    1. Chang KC, et al. Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. Crit. Care. 2013;17:R85. doi: 10.1186/cc12711.
    1. Chang K, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit. Care. 2014;18:R3. doi: 10.1186/cc13176.
    1. Mauri C, Bosma A. Immune regulatory function of B cells. Annu. Rev. Immunol. 2012;30:221–241. doi: 10.1146/annurev-immunol-020711-074934.
    1. Rauch PJ, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012;335:597–601. doi: 10.1126/science.1215173.
    1. Monserrat J, et al. Early alterations of B cells in patients with septic shock. Crit. Care. 2013;17:R105. doi: 10.1186/cc12750.
    1. Kelly-Scumpia KM, et al. B cells enhance early innate immune responses during bacterial sepsis. J. Exp. Med. 2011;208:1673–1682. doi: 10.1084/jem.20101715.
    1. Fillatreau S, et al. B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 2002;3:944–950. doi: 10.1038/ni833.
    1. Mizoguchi A, et al. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002;16:219–230. doi: 10.1016/S1074-7613(02)00274-1.
    1. Vaughan AT, Roghanian A, Cragg MS. B cells–masters of the immunoverse. Int. J. Biochem. Cell Biol. 2011;43:280–285. doi: 10.1016/j.biocel.2010.12.005.
    1. Rawlings DJ, et al. Integration of B cell responses through Toll-like receptors and antigen receptors. Nat. Rev. Immunol. 2012;12:282–294. doi: 10.1038/nri3190.
    1. Shankar-Hari M, et al. Activation-associated accelerated apoptosis of memory B cells in critically ill patients with sepsis. Crit. Care Med. 2017;45:875–882. doi: 10.1097/CCM.0000000000002380.
    1. Hotchkiss RS, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J. Immunol. 2001;166:6952–6963. doi: 10.4049/jimmunol.166.11.6952.
    1. Brinkhoff A, et al. B cell dynamics during experimental endotoxemia in humans. Biosci. Rep. 2019;39:BSR20182347. doi: 10.1042/BSR20182347.
    1. Peck-Palmer OM, et al. Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival. J. Leukoc. Biol. 2008;83:1009–1018. doi: 10.1189/jlb.0807528.
    1. Deng Q, et al. Protective effect of tubastatin A in CLP-induced lethal sepsis. Inflammation. 2018;41:2101–2109. doi: 10.1007/s10753-018-0853-0.
    1. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat. Rev. Immunol. 2014;14:154–165. doi: 10.1038/nri3605.
    1. Sakaguchi S, et al. Regulatory T cells and immune tolerance. Cell. 2008;133:775–787. doi: 10.1016/j.cell.2008.05.009.
    1. Tanoue T, Atarashi K, Honda K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 2016;16:295–309. doi: 10.1038/nri.2016.36.
    1. Cao C, et al. The role of regulatory T cells in immune dysfunction during sepsis. World J. Emerg. Med. 2015;6:5–9. doi: 10.5847/wjem.j.1920-8642.2015.01.001.
    1. Monneret G, et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit. Care Med. 2003;31:2068–2071. doi: 10.1097/01.CCM.0000069345.78884.0F.
    1. Venet F, et al. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med. 2009;35:678–686. doi: 10.1007/s00134-008-1337-8.
    1. Cavassani KA, et al. The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood. 2010;115:4403–4411. doi: 10.1182/blood-2009-09-241083.
    1. Venet F, et al. Regulatory T cell populations in sepsis and trauma. J. Leukoc. Biol. 2008;83:523–535. doi: 10.1189/jlb.0607371.
    1. Leng FY, et al. Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early-stage sepsis in ICU patients. J. Microbiol. Immunol. Infect. 2013;46:338–344. doi: 10.1016/j.jmii.2012.06.012.
    1. Cao C, et al. Toll-like receptor 4 deficiency increases resistance in sepsis-induced immune dysfunction. Int. Immunopharmacol. 2018;54:169–176. doi: 10.1016/j.intimp.2017.11.006.
    1. Cao C, et al. Ulinastatin mediates suppression of regulatory T cells through TLR4/NF-kappaB signaling pathway in murine sepsis. Int. Immunopharmacol. 2018;64:411–423. doi: 10.1016/j.intimp.2018.09.025.
    1. Carrigan SO, et al. Depletion of natural CD4+CD25+ T regulatory cells with anti-CD25 antibody does not change the course of Pseudomonas aeruginosa-induced acute lung infection in mice. Immunobiology. 2009;214:211–222. doi: 10.1016/j.imbio.2008.07.027.
    1. Venet F, et al. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr. Opin. Immunol. 2013;25:477–483. doi: 10.1016/j.coi.2013.05.006.
    1. Hotchkiss RS, et al. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J. Immunol. 1999;162:4148–4156.
    1. Watanabe E, Thampy LK, Hotchkiss RS. Immunoadjuvant therapy in sepsis: novel strategies for immunosuppressive sepsis coming down the pike. Acute Med. Surg. 2018;5:309–315. doi: 10.1002/ams2.363.
    1. Hutchins NA, et al. The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol. Med. 2014;20:224–233. doi: 10.1016/j.molmed.2014.01.002.
    1. Francisco-Cruz A, et al. Granulocyte-macrophage colony-stimulating factor: not just another haematopoietic growth factor. Med. Oncol. 2014;31:774. doi: 10.1007/s12032-013-0774-6.
    1. Meisel C, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am. J. Respir. Crit. Care Med. 2009;180:640–648. doi: 10.1164/rccm.200903-0363OC.
    1. Hall MW, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37:525–532. doi: 10.1007/s00134-010-2088-x.
    1. Docke WD, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat. Med. 1997;3:678–681. doi: 10.1038/nm0697-678.
    1. Nalos M, et al. Immune effects of interferon gamma in persistent staphylococcal sepsis. Am. J. Respir. Crit. Care Med. 2012;185:110–112. doi: 10.1164/ajrccm.185.1.110.
    1. Zhang Y, et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit. Care. 2018;14:R220. doi: 10.1186/cc9354.
    1. Zhang Y, et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit. Care. 2011;15:R70. doi: 10.1186/cc10059.
    1. Pellegrini M, et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011;144:601–613. doi: 10.1016/j.cell.2011.01.011.
    1. Yang X, et al. T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response. J. Immunol. 2013;190:2068–2079. doi: 10.4049/jimmunol.1202661.
    1. Zhao Z, et al. Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression. Clin. Exp. Immunol. 2014;178:279–291. doi: 10.1111/cei.12401.
    1. Inoue S, et al. Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock. 2011;36:38–44. doi: 10.1097/SHK.0b013e3182168cce.

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