2 research outputs found
Dysfunctional CD8(+) T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction
The transcription factor T-bet regulates the production of interferon-γ 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-γ 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-γ 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
Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy
Polyomavirus-associated nephropathy (PVAN) is a significant
complication after kidney transplantation, often leading to
premature graft loss. In order to identify antiviral responses
of the renal tubular epithelium, we studied activation of the
viral DNA and the double-stranded RNA (dsRNA) sensors
Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I
(RIG-I) in allograft biopsy samples of patients with PVAN, and
in human collecting duct cells in culture after stimulation
by the dsRNA mimic polyriboinosinic:polyribocytidylic acid
(poly(I:C)), cytokines, or infection with BK virus. Double
staining using immunofluorescence for BK virus and TLR3
showed strong signals in epithelial cells of distal cortical
tubules and the collecting duct. In biopsies microdissected to
isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA
expression was found to be increased in PVAN. Collecting
duct cells in culture expressed TLR3 intracellularly, and
activation of TLR3 and RIG-I by poly(I:C) enhanced expression
of cytokine, chemokine, and IFN-b mRNA. This inflammatory
response could be specifically blocked by siRNA to TLR3.
Finally, infection of the collecting duct cells with BK virus
enhanced the expression of cytokines and chemokines. This
led to an efficient antiviral immune response with TLR3 and
RIG-I upregulation without activation of IL-1b or components
of the inflammasome pathway. Thus, PVAN activation of
innate immune defense mechanisms through TLR3 is involved
in the antiviral and anti-inflammatory response leading to the
expression of proinflammatory cytokines and chemokines