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Chapter 10 : Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection

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Abstract:

The best-studied cytokines in terms of the understanding of their signaling for immunoregulatory effects on innate and adaptive immunity during viral infections are the type I interferons (IFNs), and certain viruses appear to preferentially induce the innate factors to high and sustained levels. Natural killer (NK)-cell cytotoxicity may also have other downstream immunoregulatory functions because viral infections can trigger profound diseases characterized by hyperactivation of macrophages and cytokine production, such as hemophagocytic lymphohistiocytosis, in mice and men with defects in the molecular mechanisms required for delivery of killing function. The cytokines help support the accumulation of plasmacytoid dendritic cells (pDCs), major contributors to type I IFN production during certain viral infections. In addition, they have effects on other DC populations thought to be important in mediating antigen-presenting cell functions for the activation of adaptive immunity, although some of these are paradoxical. Thus, type I IFNs produced during early viral infections link the immediate earliest responses to induction of innate defense mechanisms delivered by NK cells and shape the DC responses for type I IFN production and induction of adaptive immunity. To evaluate the consequences of different Stat levels on cellular responses to type I IFNs and on the endogenous immune responses to viral infections, experiments have been carried out in uninfected and lymphocytic choriomeningitis virus (LCMV)-infected immunocompetent mice and mice deficient in Stat1 or Stat2. Type I IFNs are currently being used in the treatment of chronic infections with hepatitis C virus, cancers, and multiple sclerosis.

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10

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Major Histocompatibility Complex
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Figure 1

The biological effects of type I IFNs. The innate type I IFN cytokines, IFN-α/β, have a wide range of biological effects. These are important in promoting antiviral defense mechanisms. The cytokines induce expression of a number of biochemical pathways for cellular resistance to viral infection, including the Mx, PKR, and OAS enzymes. In addition, type I IFNs have a number of immunoregulatory effects, and these can also enhance antiviral states within an infected individual. In terms of innate cell responses, the cytokines activate NK-cell cytotoxicity and promote the maturation and accumulation of different DC populations. They also have effects on the expression of other innate cytokines, including induction of IL-15, concentration-dependent enhancement or inhibition of IL-12 expression, and inhibition of NK-cell IFN-γ production. In contrast to the effects on NK cells, the type I IFNs enhance T-cell IFN-γ production, and certain of their effects on DCs can have downstream consequences for adaptive immune responses. The antiproliferative effects of the cytokines present a challenge for the expansion of antigen-specific adaptive responses. MHC, major histocompatibility complex.

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Image of Figure 2
Figure 2

Signaling pathways used by type I IFNs. The classic signaling pathway stimulated by type I IFNs results in the stimulation of Jak1 and Tyk2 to activate, by phosphorylation, Stat2 and Stat1. These, in association with IRF9, translocate to the nucleus to stimulate the expression of gene targets expressing appropriate promoter elements. The cytokines, however, can also activate Stat1/Stat1 homodimers to stimulate expression of gene targets with promoter elements for these. Furthermore, there are a total of seven Stats, Stat1 through Stat6 (including Stat5a and Stat5b), and type I IFNs have been reported to conditionally activate all of these ( ).

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Image of Figure 3
Figure 3

Schematic representation of endogenous immune responses to LCMV infection. At early times after infection with LCMV, immune-competent mice have high type I IFNs with IL-18 induction. The type I IFNs promote NK-cell cytotoxicity and elicit induction of IL-15 to result in NK-cell proliferation. There is, however, little biologically active IL-12. NK-cell IFN-γ production is also at low to undetectable levels, and NK cells become refractory to IL-12 for IFN-γ induction. At intermediate times after infection, there is an endogenous IFN-γ response produced by antigen-specific CD8 T cells, and this is dependent on type I IFNs and enhanced by IL-18. A dramatic expansion of the antigen-specific CD8 T cells is observed at late times after infection. (Presentation derived from compiled results in references , and .)

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Figure 4

Model for conditioning of the biological effects of type I IFNs by changing Stat concentrations. Taken together with the experimental evidence demonstrating that the type I IFNs can conditionally activate all of the Stats, the newer results showing that relative Stat concentrations can be regulated suggest a model for changing biological effects of the cytokines by differentially regulating Stat levels. The model implies that access to different signaling pathways is a result of total and relative concentrations of different Stats.

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Figure 5

Total and NK-cell Stat levels—consequences for responsiveness to type I IFNs. The levels of Stat4 and Stat1 were evaluated by Western blot (A) and FACS analyses (B–D) in total, NK, and non-NK cells isolated from the spleens of uninfected mice and from mice at day 1.5 and 2.5 of LCMV infection, as indicated. The responsiveness of the total and NK-cell populations to type I IFNs for activation of pStat1 (E) or pStat4 (F) was examined using cells from uninfected (day 0) or LCMV-infected (day 1.5 or 2.5) mice. After treatment with type I IFN for 90 min in culture, the populations were stained intracellularly for the pStats. Gray areas represent results from untreated cells, solid lines represent results with IFN-treated cells, and the broken lines represent isotype control staining of treated cells. (Reproduced, in modified form, from reference with permission of the Rockefeller University Press.)

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Figure 6

Changing Stat1 levels in CD8 T cells responding to LCMV infections. Cells were prepared from uninfected mice or mice infected with LCMV for the indicated times. (A) Spleen cell yields were measured and the number of CD8 and CD4 T cells determined using FACS analysis of subsets expressing cell markers. (B) Cytoplasmic staining of total Stat1 protein was determined in total cells and in the T-cell subset identified by cell surface staining with CD8. (C) To identify the cells proliferating in vivo, BrdU was administered for 2 hours prior to harvest, and the CD8 T-cell subsets were examined for expression of Stat1 along with BrdU. (Reproduced, in modified form, with permission from research originally published in reference .)

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Figure 7

Stat associations with the type I IFN receptors in total, NK, and non-NK cells. Total splenic cells, NK cells, and non-NK cells were prepared from uninfected and day 5 LCMV-infected mice. The association of Stat1 or Stat4 with their type I IFN receptor was determined by coimmunoprecipation (IP) using antibodies specific for the receptor (lanes 1 to 6). Input samples were also examined (lanes 8 to 13). The specificity of the association was confirmed by detection of immunoreactivity in cell lysates from IFNAR-, Stat1-, or Stat4-deficient cells (lanes 14 to 16). (Reproduced from reference with permission.)

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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Image of Figure 8
Figure 8

Summary of the current understanding of known Stat levels and use in NK and CD8 T cells during LCMV infections. NK cells begin with high Stat4 levels pre-associated with the type I IFN receptor. In contrast, they have little Stat1 associated with the receptor, and other cell types have little association of either Stat1 or Stat4. After infection, however, high Stat1 levels are induced in all populations, and the molecule is now associated with the receptor in NK cells as well as other cells. In the case of CD8 T cells, the receptor associations remain to be determined. Stat1 is required, however, to control nonspecific CD8 T-cell proliferation at early times after infection, and there is a preferential expansion of antigen-specific cells from within a subset expressing low Stat1 levels.

Citation: Biron C. 2009. Type I Interferon Signaling in Shaping Cellular Innate and Adaptive Immunity to Viral Infection, p 137-153. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch10
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