Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis.
Apoptosis of CD4(+) T cells and T(H)2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell-dependent IgM and IgG(2a) antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4(+) T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.
Scumpia
Philip O
PO
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610-0286, USA.
Delano
Matthew J
MJ
Kelly-Scumpia
Kindra M
KM
Weinstein
Jason S
JS
Wynn
James L
JL
Winfield
Robert D
RD
Xia
Changqing
C
Chung
Chun Shiang
CS
Ayala
Alfred
A
Atkinson
Mark A
MA
Reeves
Westley H
WH
Clare-Salzler
Michael J
MJ
Moldawer
Lyle L
LL
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007154:Immune System Diseases / Q000188:drug therapy* / Q000209:etiology; D007110:Immunity, Active / Q000187:drug effects*; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology
D000906:Antibodies; D017252:CD3 Complex; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse
Science. 2003 Feb 14;299(5609):1033-6
12532024
J Immunol. 2007 Jun 1;178(11):6715-9
17513716
Eur J Immunol. 2004 Mar;34(3):613-22
14991590
J Immunol. 2004 Apr 15;172(8):4686-90
15067043
J Immunol. 2004 May 15;172(10):6065-73
15128790
Cancer Res. 2004 Aug 15;64(16):5839-49
15313928
Nat Rev Immunol. 2004 Sep;4(9):675-87
15343367
Ann Surg. 1975 Sep;182(3):207-17
126046
Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13119-24
8917554
Nat Med. 1997 Jun;3(6):678-81
9176497
Ann Surg. 1997 Oct;226(4):450-8; discussion 458-60
9351713
J Immunol. 1999 Apr 1;162(7):4148-56
10201940
Eur J Immunol. 2005 Apr;35(4):1016-22
15770698
Am J Surg. 1999 Oct;178(4):288-92
10587185
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14541-6
10588741
Arch Surg. 1999 Dec;134(12):1317-23; discussion 1324
10593329
Nat Immunol. 2000 Dec;1(6):496-501
11101871
Mol Cell Biol. 2001 May;21(9):3206-19
11287624
Clin Cancer Res. 2001 Mar;7(3 Suppl):958s-965s
11300497
J Immunol. 2001 May 1;166(9):5495-507
11313388
Nat Immunol. 2002 Feb;3(2):135-42
11812990
J Immunol. 2005 Jun 1;174(11):7141-6
15905557
Blood. 2005 Oct 1;106(7):2295-301
15941915
J Immunol. 2006 Feb 15;176(4):2085-94
16455964
J Immunol. 2006 Jun 15;176(12):7278-87
16751371
Immunity. 2006 Nov;25(5):783-93
17055754
J Immunol. 2006 Dec 1;177(11):7943-9
17114466
J Immunol. 2006 Dec 1;177(11):7968-73
17114469
Shock. 2007 Mar;27(3):251-7
17304105
N Engl J Med. 2003 Apr 17;348(16):1546-54
12700374