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Critical Care
Published in: Critical Care 3/2012

Open Access 01-06-2012 | Research

A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis

Authors: Jonathan S Boomer, Jennifer Shuherk-Shaffer, Richard S Hotchkiss, Jonathan M Green

Published in: Critical Care | Issue 3/2012

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Abstract

Introduction

Severe sepsis is characterized by an initial hyper-inflammatory response that may progress to an immune-suppressed state associated with increased susceptibility to nosocomial infection. Analysis of samples obtained from patients who died of sepsis has identified expression of specific inhibitory receptors expressed on lymphocytes that are associated with cell exhaustion. The objective of this study was to prospectively determine the pattern of expression of these receptors and immune cell function in patients with acute sepsis.

Methods

Twenty-four patients with severe sepsis were enrolled within 24 hours of the onset of sepsis, as were 12 age-matched healthy controls. Peripheral blood was obtained at enrollment and again seven days later. Immune cell subsets and receptor expression were extensively characterized by quantitative flow cytometry. Lymphocyte function was assayed by stimulated cytokine secretion and proliferation assays. Results were also correlated to clinical outcome.

Results

At the onset of severe sepsis, patients had decreased circulating innate and adaptive immune cells and elevated lymphocyte expression of receptors associated with cell activation compared to controls. Samples analyzed seven days later demonstrated increased expression of the inhibitory receptors CTLA4, TIM-3 and LAG-3 on T lymphocytes accompanied by decreased expression of the IL-7 receptor. Functional assays revealed impaired secretion of interferon γ following stimulation in vitro, which was reversible by incubation overnight in fresh media. Impaired secretion of IFNγ correlated with death or development of secondary infection.

Conclusions

Lymphocytes from patients with acute sepsis upregulate expression of receptors associated with cell exhaustion, which may contribute to the immune suppressed state that occurs in protracted disease. Therapy that reverses T cell exhaustion may restore immune function in immunocompromised patients and improve survival in sepsis.
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Literature
1.
2.
3.
Bone RC, Grodzin CJ, Balk RA: Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997, 112: 235-243. 10.1378/chest.112.1.235CrossRefPubMed
4.
Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, Lepage E, Le Gall R: Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002, 28: 108-121. 10.1007/s00134-001-1143-zCrossRefPubMed
5.
Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA: The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009, 15: 496-497. 10.1038/nm0509-496PubMedCentralCrossRefPubMed
6.
Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008, 300: 413-422. 10.1001/jama.300.4.413PubMedCentralCrossRefPubMed
7.
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999, 27: 1230-1251. 10.1097/00003246-199907000-00002CrossRefPubMed
8.
Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P, Xanthoudakis S, Roy S, Black C, Grimm E, Aspiotis R, Han Y, Nicholson DW, Karl IE: Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000, 1: 496-501. 10.1038/82741CrossRefPubMed
9.
Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG, Karl IE: Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001, 166: 6952-6963.CrossRefPubMed
10.
Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, Cobb JP, Coopersmith C, Karl IE: Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002, 168: 2493-2500.CrossRefPubMed
11.
Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, Volk HD, Kox W: Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997, 3: 678-681. 10.1038/nm0697-678CrossRefPubMed
12.
Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P: Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006, 32: 1175-1183. 10.1007/s00134-006-0204-8CrossRefPubMed
13.
Nolan A, Kobayashi H, Naveed B, Kelly A, Hoshino Y, Hoshino S, Karulf MR, Rom WN, Weiden MD, Gold JA: Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis. PLoS One 2009, 4: e6600. 10.1371/journal.pone.0006600PubMedCentralCrossRefPubMed
14.
Wisnoski N, Chung CS, Chen Y, Huang X, Ayala A: The contribution of CD4+ CD25+ T-regulatory-cells to immune suppression in sepsis. Shock 2007, 27: 251-257. 10.1097/01.shk.0000239780.33398.e4PubMedCentralCrossRefPubMed
15.
Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, Ulfman LH, Leenen LP, Pickkers P, Koenderman L: A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest 2012, 122: 327-336. 10.1172/JCI57990PubMedCentralCrossRefPubMed
16.
Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C, Poitevin F, Bohe J, Lepape A, Ayala A, Monneret G: Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med 2009, 35: 678-686. 10.1007/s00134-008-1337-8PubMedCentralCrossRefPubMed
17.
Venet F, Chung C-S, Monneret G, Huang X, Horner B, Garber M, Ayala A: Regulatory T cell populations in sepsis and trauma. J Leukoc Biol 2008, 83: 523-535.CrossRefPubMed
18.
Gabrilovich DI, Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. 2009, 9: 162-174.
19.
Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O'Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL: MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 2007, 204: 1463-1474. 10.1084/jem.20062602PubMedCentralCrossRefPubMed
20.
Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS: Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011, 306: 2594-2605. 10.1001/jama.2011.1829PubMedCentralCrossRefPubMed
21.
Moskophidis D, Lechner F, Pircher H, Zinkernagel RM: Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993, 362: 758-761. 10.1038/362758a0CrossRefPubMed
22.
Robinson HL: T cells versus HIV-1: fighting exhaustion as well as escape. Nat Immunol 2003, 4: 12-13. 10.1038/ni0103-12CrossRefPubMed
23.
Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ: Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 2004, 172: 4204-4214.CrossRefPubMed
24.
Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C: PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006, 80: 11398-11403. 10.1128/JVI.01177-06PubMedCentralCrossRefPubMed
25.
26.
27.
Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006, 443: 350-354. 10.1038/nature05115CrossRefPubMed
28.
Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH: Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 2006, 203: 2223-2227. 10.1084/jem.20061800PubMedCentralCrossRefPubMed
29.
Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF: Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood 2009, 114: 1528-1536. 10.1182/blood-2008-09-179697CrossRefPubMed
30.
Watanabe T, Bertoletti A, Tanoto TA: PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat 2010, 17: 453-458.CrossRefPubMed
31.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31: 1250-1256. 10.1097/01.CCM.0000050454.01978.3BCrossRefPubMed
32.
Andaluz-Ojeda D, Bobillo F, Iglesias V, Almansa R, Rico L, Gandia F, Resino S, Tamayo E, de Lejarazu RO, Bermejo-Martin JF: A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine 2012, 57: 332-336. 10.1016/j.cyto.2011.12.002CrossRefPubMed
33.
Adib-Conquy M, Cavaillon JM: Compensatory anti-inflammatory response syndrome. Thromb Haemost 2009, 101: 36-47.PubMed
34.
Schwulst SJ, Muenzer JT, Peck-Palmer OM, Chang KC, Davis CG, McDonough JS, Osborne DF, Walton AH, Unsinger J, McDunn JE, Hotchkiss RS: Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock 2008, 30: 127-134.PubMed
35.
Weber SU, Schewe JC, Lehmann LE, Muller S, Book M, Klaschik S, Hoeft A, Stuber F: Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis. Crit Care 2008, 12: R128. 10.1186/cc7088PubMedCentralCrossRefPubMed
36.
Venet F, Bohe J, Debard AL, Bienvenu J, Lepape A, Monneret G: Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock. Crit Care Med 2005, 33: 2836-2840. 10.1097/01.CCM.0000189745.66585.AECrossRefPubMed
37.
Venet F, Davin F, Guignant C, Larue A, Cazalis MA, Darbon R, Allombert C, Mougin B, Malcus C, Poitevin-Later F, Lepape A, Monneret G: Early assessment of leukocyte alterations at diagnosis of septic shock. Shock 2010, 34: 358-363. 10.1097/SHK.0b013e3181dc0977CrossRefPubMed
38.
Ayala A, Perl M, Venet F, Lomas-Neira J, Swan R, Chung CS: Apoptosis in sepsis: mechanisms, clinical impact and potential therapeutic targets. Curr Pharm Des 2008, 14: 1853-1859. 10.2174/138161208784980617CrossRefPubMed
39.
Chung CS, Venet F, Chen Y, Jones LN, Wilson DC, Ayala CA, Ayala A: Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival. Shock 2010, 34: 150-161. 10.1097/SHK.0b013e3181cf70fbPubMedCentralCrossRefPubMed
40.
Cheron A, Floccard B, Allaouchiche B, Guignant C, Poitevin F, Malcus C, Crozon J, Faure A, Guillaume C, Marcotte G, Vulliez A, Monneuse O, Monneret G: Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care 2010, 14: R208. 10.1186/cc9331PubMedCentralCrossRefPubMed
41.
Landelle C, Lepape A, Voirin N, Tognet E, BoFhé J, Vanhems P, Monneret G: Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 2010, 36: 1859-1866. 10.1007/s00134-010-1962-xCrossRefPubMed
42.
Venet F, Lepape A, Monneret G: Clinical review: flow cytometry perspectives in the ICU - from diagnosis of infection to monitoring of injury-induced immune dysfunctions. Crit Care 2011, 15: 231. 10.1186/cc10333PubMedCentralCrossRefPubMed
43.
Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, Hanson HL, Steinberg JP, Masopust D, Eherry EJ, Altman JD, Rouse BT, Freeman GJ, Ahmed R, Grakoui A: Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 2007, 81: 2545-2553. 10.1128/JVI.02021-06PubMedCentralCrossRefPubMed
44.
El-Far M, Halwani R, Said E, Trautmann L, Doroudchi M, Janbazian L, Fonseca S, van Grevenynghe J, Yassine-Diab B, Sekaly RP, Haddad EK: T-cell exhaustion in HIV infection. Curr HIV/AIDS Rep 2008, 5: 13-19. 10.1007/s11904-008-0003-7CrossRefPubMed
45.
Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L, Cavallo MC, Silini EM, Andreone P, Missale G, Ferrari C: Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010, 138: 682-693. 10.1053/j.gastro.2009.09.052CrossRefPubMed
46.
Rodrigue-Gervais IG, Rigsby H, Jouan L, Sauve D, Sekaly RP, Willems B, Lamarre D: Dendritic cell inhibition is connected to exhaustion of CD8+ T cell polyfunctionality during chronic hepatitis C virus infection. J Immunol 2010, 184: 3134-3144. 10.4049/jimmunol.0902522CrossRefPubMed
47.
48.
Nolan A, Weiden M, Kelly A, Hoshino Y, Hoshino S, Mehta N, Gold JA: CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. Am J Respir Crit Care Med 2008, 177: 301-308.PubMedCentralCrossRefPubMed
49.
Frebel H, Richter K, Oxenius A: How chronic viral infections impact on antigen-specific T-cell responses. Eur J Immunol 2010, 40: 654-663. 10.1002/eji.200940102CrossRefPubMed
50.
51.
Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS: Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 2010, 88: 233-240. 10.1189/jlb.0110037CrossRefPubMed
52.
Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F, Malcus C, Cheron A, Allaouchiche B, Gueyffier F, Ayala A, Monneret G, Venet F: Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 2011, 15: R99. 10.1186/cc10112PubMedCentralCrossRefPubMed
53.
Zhang Y, Li J, Lou J, Zhou Y, Bo L, Zhu J, Zhu K, Wan X, Cai Z, Deng X: Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 2011, 15: R70. 10.1186/cc10059PubMedCentralCrossRefPubMed
54.
Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K, Wan X, Deng X, Cai Z: PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care 2010, 14: R220. 10.1186/cc9354PubMedCentralCrossRefPubMed
55.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000, 192: 1027-1034. 10.1084/jem.192.7.1027PubMedCentralCrossRefPubMed
56.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006, 439: 682-687. 10.1038/nature04444CrossRefPubMed
57.
Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, S Subramaniam S, Blattman JN, Barber DL, Ahmed R: Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007, 27: 670-684. 10.1016/j.immuni.2007.09.006CrossRefPubMed
58.
Scumpia PO, Delano MJ, Kelly KM, O'Malley KA, Efron PA, McAuliffe PF, Brusko T, Ungaro R, Barker T, Wynn JL, Atkinson MA, Reeves WH, Salzler MJ, Moldawer LL: Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol 2006, 177: 7943-7949.CrossRefPubMed
59.
Venet F, Pachot A, Debard A-L, Bohe J, Bienvenu J, Lepape A, Powell WS, Monneret G: Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 2006, 177: 6540-6547.CrossRefPubMed
60.
Cavassani KA, Carson WF, Moreira AP, Wen H, Schaller MA, Ishii M, Lindell DM, Dou Y, Lukacs NW, Keshamouni VG, Hogaboam CM, Kunkel SL: The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 2010, 115: 4403-4411. 10.1182/blood-2009-09-241083PubMedCentralCrossRefPubMed
61.
Fu Q, Cui N, Yu W, Du C: Percentages of CD4+ T regulatory cells and HLA-DR expressing monocytes in severe intra-abdominal infections. Scand J Infect Dis 2010, 42: 475-478. 10.3109/00365541003660021CrossRefPubMed
62.
Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, Monneret G: Increased percentage of CD4+CD25+ regulatory T cells during septic shock is due to the decrease of CD4+CD25- lymphocytes. Crit Care Med 2004, 32: 2329-2331.PubMed
Metadata
Title
A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis
Authors
Jonathan S Boomer
Jennifer Shuherk-Shaffer
Richard S Hotchkiss
Jonathan M Green
Publication date
01-06-2012
Publisher
BioMed Central
Published in
Critical Care / Issue 3/2012
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc11404

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