TY - JOUR
T1 - Dysfunctional CD8(+) T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction
AU - Kurktschiev, Peter D.
AU - Raziorrouh, Bijan
AU - Schraut, Winfried
AU - Backmund, Markus
AU - Waechtler, Martin
AU - Wendtner, Clemens-Martin
AU - Bengsch, Bertram
AU - Thimme, Robert
AU - Denk, Gerald
AU - Zachoval, Reinhart
AU - Dick, Andrea
AU - Spannagl, Michael
AU - Haas, Juergen
AU - Diepolder, Helmut M.
AU - Jung, Maria-Christina
AU - Gruener, Norbert H.
PY - 2014/9/15
Y1 - 2014/9/15
N2 - The transcription factor T-bet regulates the production of interferon-gamma and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-gamma production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-gamma response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
AB - The transcription factor T-bet regulates the production of interferon-gamma and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-gamma production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-gamma response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
KW - RECOMBINANT HUMAN INTERLEUKIN-12
KW - VIRUS-INFECTION
KW - TRANSCRIPTION FACTOR
KW - VIRAL CLEARANCE
KW - PHASE I/II
KW - RESPONSES
KW - EFFECTOR
KW - DIFFERENTIATION
KW - EXPRESSION
KW - PROLIFERATION
U2 - 10.1084/jem.20131333
DO - 10.1084/jem.20131333
M3 - Article
SN - 0022-1007
VL - 211
SP - 2047
EP - 2059
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -