Interferon enhances the susceptibility of virus-infected fibroblasts to cytotoxic T cells.

Bukowski, Jack F.; Welsh, Raymond M.

doi:10.1084/jem.161.1.257

Cited by 88 publications

(25 citation statements)

References 15 publications

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“…This result suggests that a second factor that is produced by these cells in response to tumor necrosis factor actually induces the increase in P2-M expression. Type I interfer ons, a and p, also produced by activated monocytes, induce increased expression of class 1 major histocompatibility molecules on endothelial cells, fibroblasts, and lym phoid cells [62][63][64]. The interferon-induced increase of P2-M mRNA by these cells was not blocked by cycloheximide [62], Thus, in addition to direct production of P2-M by activated monocytes, these cells may induce p2-M production through their soluble me diators.…”

Section: Discussionmentioning

confidence: 94%

Beta-2-Microglobulin Synthesis Is Increased during Activation of Human Monocytes

Knudsen

Ng²,

Liu³

1988

Blood Purif

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We have investigated the regulation of β₂-microglobulin (β₂-M) synthesis by monocytes. Recent interest in β₂-M has developed since the discovery that this protein forms amyloid fibrils in patients undergoing long-term, chronic hemodialysis. The β₂-M amyloid-osis is linked to the greatly elevated levels of monomeric β₂-M in their circulation. Since factors that govern β₂-M release from plasma membranes are not known, we endeavored to evaluate β₂-M release during monocyte activation. Utilizing a human monocyte-like cell line, U937, we studied the effect of bacterial toxin stimulation on levels of membrane, cell surface, and supernatant β₂-M. We now present a novel method to purify β₂-M, a solid-phase radioimmunoassay to measure soluble β₂-M, and an ELISA to measure membrane β₂-M. Using these methods we found that the levels of β₂-M in the cell membrane or on the cell surface did not change during monocyte activation. However, activation did induce a significant increase in the concentration of β₂-M in monocyte supernatants, indicating that β₂-M synthesis by monocytes is increased during monocyte activation. These results suggest that monocyte activation by hemodialysis membranes may be a contributing factor to the observed increase in circulating β₂-M levels.

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Section: Discussionmentioning

confidence: 94%

Beta-2-Microglobulin Synthesis Is Increased during Activation of Human Monocytes

Knudsen

Ng²,

Liu³

1988

Blood Purif

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“…Nevertheless, it is possible that combinations of IFN-γ, IL-12, IL-15, and IL-18 signals sensitize P14 CD8 T cells, because combinations of these cytokines can promote IFN-γ production by effector and memory CD8 T cells better than any of them individually (33, 34). Due to the requirement for MHC I, it is probable that one indirect role of IFN-αβ during PV infection or poly(I:C) treatment is to up-regulate expression of MHC I. T cells are positively and then negatively selected in the thymus under conditions when IFN is not up-regulating MHC, and it has been a mystery why T cells selected at one threshold of MHC do not become auto-aggressive during viral infections which induce high levels of MHC expression throughout the host (44). Here we show that these T cells may become sensitized but not fully activated by the enhanced expression of self-MHC during acute viral infections.…”

Section: Discussionmentioning

confidence: 99%

IFN-αβ and Self-MHC Divert CD8 T Cells into a Distinct Differentiation Pathway Characterized by Rapid Acquisition of Effector Functions

Marshall

Prince

Berg

et al. 2010

The Journal of Immunology

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Non-virus-specific bystander CD8 T cells bathe in an inflammatory environment during viral infections. To determine if bystander CD8 T cells are affected by these environments, we examined P14, HY, and OT-I TCR transgenic CD8 T cells sensitized in vivo by IFN-αβ-inducing viral infections or by poly(I:C). These sensitized cells rapidly exerted effector functions such as IFN-γ production and degranulation on contact with their high affinity cognate antigen. Sensitization required self-MHC I and indirect effects of IFN-αβ, which together up-regulated the t-box transcription factor Eomesodermin, potentially enabling the T cells to rapidly transcribe CTL effector genes and behave like memory rather than naïve T cells. IL-12, IL-15, IL-18, and IFN-γ were not individually required for sensitization to produce IFN-γ, but IL-15 was required for up-regulation of granzyme B. These experiments indicate that naïve CD8 T cells receive signals from self-MHC and IFN-αβ and that by this process CD8 T cell responses to viral infection can undergo distinct differentiation pathways, depending on the timing of antigen encounter during the virus-induced IFN response.

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“…Class 1 MHC molecules are involved in antigen presentation by antigen-presenting cells to cytotoxic T lymphocytes (CTL) (33), and the possibility of increased T cell-mediated synovial cell lysis in the inflammatory microenvironment of RA joints is purely speculative at this time. Precedence for this concept comes from studies in which I F N y stimulated virus-infected fibroblasts, which expressed more class I MHC antigen, were more susceptible to CTL-mediated lysis than were comparable non-IFN y induced fibroblasts (34). A report on the in vitro interaction between CTL and a transformed synovial cell line has begun to address this hypothesis (35).…”

Section: Discussionmentioning

confidence: 99%

Role of cytokines in inflammatory synovitis

Chin

Winterrowd

Krzesicki

et al. 1990

Arthritis & Rheumatism

118

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This study was undertaken in an effort to understand the role of cytokines in T lymphocyte trafficking into inflamed synovium and in the potential enhancement of antigen presentation by human synovial fibroblasts. We found that interleukin-lp (IL-lp), tumor necrosis factor a (TNFa), and interferon-y (IFNy) each increased the cell surface expression of intercellular adhesion molecule I (ICAM-I) on human synovial fibroblasts in a dose-and time-dependent manner. Maximal ICAM-1 expression occurred within 8 hours of induction, with the following order of efficacy: IFNy > TNFa > IL-1p. The number of cells bearing the ICAM-1 antigen also increased, from a basal level of -30% to more than 83% after cytokine induction (for all 3 cytokines). ICAM-1 expression rapidly decreased fdlowing cytokine removal. The expression of lymphocyte function-associated antigen 3 was also examined, but it was not changed by any of the 3 cytokines. Class I major histocompatibility complex antigen expression was increased modestly by all 3 cytokines, and expression was maximal by 24 hours after treatment. Only IFNy induced HLA class I1 antigen expression, and this expression persisted for up to 6 days following removal of the lymphokine. IL-6 and granulocyte-macrophage colony- stimulating factor had no effect on any of the parameters examined. Our data support an interactive role for inflammatory cytokines and the expression of adhesion ligands and HLA antigens by human synovial fibroblasts in the pathogenesis of synovial inflammation in rheumatoid arthritis.Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized in part by the proliferation of pannus tissue in diseased joints, which leads to eventual degradation of the articular cartilage and the subchondral bone (1)(2)(3). It has been demonstrated that the RA synovium contains cells that express HLA-DR antigens (4-7). There is also evidence that indicates that cells populating the inflamed tissue lining the RA joint have adhesion molecules as ligands for homing receptors on circulating T lymphocytes (8,9). It is hypothesized that the increased adhesiveness of the inflamed synovial tissue may play a central role in lymphocyte homing and retention in the diseased joint. The current study was initiated in an effort to elucidate cellular mechanisms that may be involved in chronic inflammatory synovitis. We examined the time and dose effects of various cytokines present in the inflammatory microenvironment in RA (10) on the expression of adhesion ligands intercellular adhesion molecule I (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3), and the expression of class I and class I1 major histocompatibility complex (MHC) antigens, 4 fibroblast cell surface molecules whose regulation may play critical roles in synovial inflammation.In previous studies, interferon-y (IFNy) has been shown to induce the expression of class I1 MHC antigens on synovial fibroblasts (1 l), and ICAM-1 has MATERIALS AND METHODSRecombinant cytokines and antibodies. Recombinant human i...

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Interferon enhances the susceptibility of virus-infected fibroblasts to cytotoxic T cells.

Cited by 88 publications

References 15 publications

Beta-2-Microglobulin Synthesis Is Increased during Activation of Human Monocytes

Beta-2-Microglobulin Synthesis Is Increased during Activation of Human Monocytes

IFN-αβ and Self-MHC Divert CD8 T Cells into a Distinct Differentiation Pathway Characterized by Rapid Acquisition of Effector Functions

Role of cytokines in inflammatory synovitis

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