Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent
Benyue Zhang, … , Joshy Jacob, Robert S. Mittler
Benyue Zhang, … , Joshy Jacob, Robert S. Mittler
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3029-3041. https://doi.org/10.1172/JCI32426.
View: Text | PDF
Research Article Virology

Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent

Abstract

CD137 is expressed on activated T cells and ligands to this costimulatory molecule have clinical potential for amplifying CD8 T cell immunity to tumors and viruses, while suppressing CD4 autoimmune T cell responses. To understand the basis for this dichotomy in T cell function, CD4 and CD8 antiviral immunity was measured in lymphocytic choriomeningitis virus (LCMV) Armstrong– or A/PR8/34 influenza–infected mice injected with anti-CD137 mAbs. We found that the timing of administration of anti-CD137 mAbs profoundly altered the nature of the antiviral immune response during acute infection. Antiviral immunity progressed normally for the first 72 hours when the mAb was administered early in infection before undergoing complete collapse by day 8 postinfection. Anti-CD137–injected LCMV-infected mice became tolerant to, and persistently infected with, LCMV Armstrong. Elevated levels of IL-10 early in the response was key to the loss of CD4+ T cells, whereas CD8+ T cell deletion was dependent on a prolonged TNF-α response, IL-10, and upregulation of Fas. Blocking IL-10 function rescued CD4 antiviral immunity but not CD8+ T cell deletion. Anti-CD137 treatment given beyond 72 hours after infection significantly enhanced antiviral immunity. Mice treated with anti-CD137 mAb 1 day before infection with A/PR8/34 virus experienced 80% mortality compared with 40% mortality of controls. When treatment was delayed until day 1 postinfection, 100% of the infected mice survived. These data show that anti-CD137 mAbs can induce T cell activation–induced cell death or enhance antiviral immunity depending on the timing of treatment, which may be important for vaccine development.

Authors

Benyue Zhang, Charles H. Maris, Juergen Foell, Jason Whitmire, Liguo Niu, Jing Song, Byoung S. Kwon, Anthony T. Vella, Rafi Ahmed, Joshy Jacob, Robert S. Mittler

×

Figure 1

Anti-CD137 mAbs suppress antiviral immunity.

Options: View larger image (or click on image) Download as PowerPoint
Anti-CD137 mAbs suppress antiviral immunity. An acute viral infection wa...
An acute viral infection was generated in C57BL/6 mice by injecting 2 × 105 PFU LCMV Armstrong i.p. followed by injection of 200 μg α-CD137 (clone 3H3) or rat IgG by i.p. on day 1 P.I. (A) Reduction in virus-specific T cell–dependent humoral immunity on days 8 and 30 P.I. (B) Marked reduction in the number of virus-specific antibody-secreting cells in bone marrow at day 30 P.I. (C) CD4+ T cells were unable to produce IFN-γ following in vitro peptide restimulation with CD4-restricted immunodominant LCMV-derived peptides on day 8 P.I. (D) On day 8 P.I. antiviral CD8+ T cell expansion was determined by DbNP396-404 tetramer staining and CD43 upregulation on virus-activated T cells. (E) Absolute numbers of NP396-404+ CD8+ T cells were enumerated following FACS analysis of tetramer-stained T cells. (F) IFN-γ staining was measured following in vitro NP396-404 peptide restimulation and ICS with a FITC-conjugated anti–IFN-γ mAb. (G) CTL responses against NP396-404 peptide–pulsed MC57 cells were measured ex vivo from naive mice (lines), LCMV-infected anti-CD137–injected mice (diamonds), LCMV-infected rat IgG–injected mice (circles), and LCMV-infected untreated mice (squares). E:T, effector to target ratio. Data are from 1 representative experiment of 3. (H) LCMV-specific CD8+ T cell responses to immunodominant epitopes were 105 IFN-γ+ T cells/spleen, subdominant epitopes were 104 IFN-γ+ T cells/spleen on day 30 P.I. by measuring IFN-γ production in response to in vitro peptide restimulation, ICS, and FACS analysis.