CD40 activation rescues antiviral CD8⁺ T cells from PD-1-mediated exhaustion.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Adaptive Immunity* ; Host-Pathogen Interactions*; CD40 Antigens/*agonists ; CD8-Positive T-Lymphocytes/*immunology ; Hepatitis B/*immunology ; Hepatitis B virus/*physiology ; Programmed Cell Death 1 Receptor/*metabolism; Animals ; Antigen Presentation ; Antigens, Differentiation/genetics ; Antigens, Differentiation/metabolism ; Antigens, Viral/metabolism ; CD40 Antigens/genetics ; CD40 Antigens/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/virology ; Cell Differentiation ; Cell Proliferation ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/pathology ; Dendritic Cells/virology ; Gene Expression Regulation, Viral ; Hepatitis B/metabolism ; Hepatitis B/pathology ; Hepatitis B/virology ; Hepatitis B virus/immunology ; Liver/immunology ; Liver/metabolism ; Liver/pathology ; Liver/virology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Programmed Cell Death 1 Receptor/genetics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/metabolism ; T-Lymphocytes, Cytotoxic/pathology ; T-Lymphocytes, Cytotoxic/virology

The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation.

Erratum in: PLoS Pathog. 2016 Dec 7;12 (12 ):e1006086. (PMID: 27926947)
Erratum in: PLoS Pathog. 2017 May 31;13(5):e1006416. (PMID: 28562694)

Nature. 1998 Jun 4;393(6684):478-80. (PMID: 9624004)
J Virol. 2007 Apr;81(8):4215-25. (PMID: 17287266)
Blood. 2008 Oct 15;112(8):3175-85. (PMID: 18669892)
Immunity. 2005 Jul;23(1):53-63. (PMID: 16039579)
Virology. 2005 Mar 15;333(2):293-300. (PMID: 15721363)
N Engl J Med. 2004 Mar 11;350(11):1118-29. (PMID: 15014185)
J Exp Med. 2005 Sep 5;202(5):637-50. (PMID: 16129706)
J Immunol. 1994 Jul 15;153(2):482-8. (PMID: 8021489)
Immunology. 2002 Jun;106(2):127-38. (PMID: 12047742)
Nat Immunol. 2009 Jan;10(1):29-37. (PMID: 19043418)
Nat Immunol. 2003 Nov;4(11):1102-10. (PMID: 14556006)
Hepatology. 2012 Jan;55(1):287-97. (PMID: 21898480)
Hepatology. 2009 Aug;50(2):612-21. (PMID: 19575456)
Eur J Immunol. 1998 Jan;28(1):221-36. (PMID: 9485202)
Nature. 2004 Jan 8;427(6970):154-9. (PMID: 14712275)
J Virol. 1995 Oct;69(10):6158-69. (PMID: 7666518)
J Immunol. 2002 Nov 1;169(9):5188-95. (PMID: 12391236)
Immunity. 2009 Jul 17;31(1):145-57. (PMID: 19604493)
J Virol. 2002 Sep;76(17):8609-20. (PMID: 12163580)
Annu Rev Immunol. 2002;20:551-79. (PMID: 11861612)
PLoS Pathog. 2013 Mar;9(3):e1003208. (PMID: 23516358)
Histochem Cell Biol. 2008 Apr;129(4):441-51. (PMID: 18214516)
Hepatology. 2011 May;53(5):1494-503. (PMID: 21360567)
J Clin Invest. 2004 Sep;114(5):701-12. (PMID: 15343389)
J Immunol. 2007 Mar 1;178(5):2714-20. (PMID: 17312113)
Immunity. 2007 Jan;26(1):117-29. (PMID: 17239632)
Int Immunol. 1997 Aug;9(8):1203-12. (PMID: 9263018)
Cytokine Growth Factor Rev. 1997 Dec;8(4):313-32. (PMID: 9620644)
Immunogenetics. 2000 Nov;52(1-2):35-45. (PMID: 11132155)
Nature. 1998 Jun 4;393(6684):474-8. (PMID: 9624003)
Immunity. 1996 Oct;5(4):319-30. (PMID: 8885865)
Proc Natl Acad Sci U S A. 1987 Oct;84(19):6909-13. (PMID: 3477814)
Nat Rev Immunol. 2001 Nov;1(2):126-34. (PMID: 11905820)
J Immunol. 2001 May 1;166(9):5430-8. (PMID: 11313380)
Hepatology. 2010 Dec;52(6):1934-47. (PMID: 21064032)
Nat Rev Immunol. 2003 Jan;3(1):51-62. (PMID: 12511875)
Eur J Immunol. 1994 Dec;24(12):3106-12. (PMID: 7528669)
Annu Rev Immunol. 1995;13:29-60. (PMID: 7612225)
Eur J Immunol. 2005 Oct;35(10):2970-81. (PMID: 16163670)
Nat Rev Immunol. 2010 Nov;10(11):753-66. (PMID: 20972472)
Science. 1995 Nov 10;270(5238):985-8. (PMID: 7481803)
Annu Rev Immunol. 2006;24:519-40. (PMID: 16551258)
J Virol. 1989 Dec;63(12):5399-404. (PMID: 2685356)
Hepatology. 2006 Nov;44(5):1182-90. (PMID: 17058232)
J Exp Med. 1993 Nov 1;178(5):1541-54. (PMID: 8228807)
Eur J Immunol. 2008 Oct;38(10):2776-83. (PMID: 18825750)
Hepatology. 2008 Jan;47(1):296-305. (PMID: 17975811)
Hepatology. 2008 Sep;48(3):978-90. (PMID: 18712788)
J Immunol. 2009 Feb 15;182(4):1901-11. (PMID: 19201843)
Nat Med. 2006 Nov;12(11):1301-9. (PMID: 17041596)
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3018-23. (PMID: 20133700)
J Virol. 2009 Oct;83(19):9652-62. (PMID: 19625407)
J Immunol. 2007 Oct 15;179(8):5064-70. (PMID: 17911591)
PLoS One. 2012;7(10):e47648. (PMID: 23112829)
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14733-8. (PMID: 20679213)
Gastroenterology. 2010 Feb;138(2):682-93, 693.e1-4. (PMID: 19800335)
J Virol. 2003 Jan;77(1):68-76. (PMID: 12477811)
J Immunol. 1994 Apr 1;152(7):3245-53. (PMID: 8144915)
J Immunol. 1998 Dec 1;161(11):5842-50. (PMID: 9834062)
J Immunol Methods. 1995 Mar 27;180(2):273-80. (PMID: 7714342)
Immunity. 2011 Aug 26;35(2):285-98. (PMID: 21856186)
J Virol. 1994 Sep;68(9):5469-75. (PMID: 8057429)
J Exp Med. 2002 May 6;195(9):1089-101. (PMID: 11994415)
Immunity. 1996 Jan;4(1):25-36. (PMID: 8574849)
J Leukoc Biol. 1996 Sep;60(3):337-44. (PMID: 8830790)
J Immunol Methods. 1994 Sep 14;174(1-2):83-93. (PMID: 8083541)
Immunity. 2006 Sep;25(3):455-71. (PMID: 16973386)
J Exp Med. 2003 May 5;197(9):1141-51. (PMID: 12732656)
Annu Rev Immunol. 2007;25:171-92. (PMID: 17129182)
Immunity. 2008 Sep 19;29(3):464-75. (PMID: 18789731)
Nature. 1999 Mar 4;398(6722):77-80. (PMID: 10078533)
Nature. 1998 Jun 4;393(6684):480-3. (PMID: 9624005)
Nat Immunol. 2003 Nov;4(11):1093-101. (PMID: 14556005)
Nat Med. 2000 Dec;6(12):1348-54. (PMID: 11100119)
Nature. 1983 Apr 7;302(5908):490-5. (PMID: 6835382)

R01 AI079060 United States AI NIAID NIH HHS; R01 CA040489 United States CA NCI NIH HHS

0 (Antigens, Differentiation)
0 (Antigens, Viral)
0 (CD40 Antigens)
0 (Pdcd1 protein, mouse)
0 (Programmed Cell Death 1 Receptor)
0 (Receptors, Antigen, T-Cell)

Date Created: 20130716 Date Completed: 20140218 Latest Revision: 20211021

20221213

PMC3708877

10.1371/journal.ppat.1003490

23853599