Induction of type I interferons and viral immunity
Author: Hidmark, Åsa
Date: 2007-06-01
Location: Gard Aulan, SMI (Entrén), Karolinska Institutet, Solna
Time: 09.30
Department: Institutionen för mikrobiologi, tumör- och cellbiologi / Department of Microbiology, Tumor and Cell Biology
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Abstract
Virus-induced type I interferons (IFNα/β) are key mediators of innate
immunity and important modulators of adaptive immunity. Early recognition
of virus and induction of IFNα/β are important for limiting the spread of
the virus. In paper I and II, we use RNA viruses, Semliki Forest virus
(SFV) and Rotavirus, to investigate which viral functions and what
cellular pathways are required for the induction of IFNα/β-production in
murine bone marrow-derived myeloid dendritic cells (mDC). We show that
both SFV and Rotavirus induce IFNα/β production via a toll-like
receptor-independent pathway and IFNα/β induction in mDC by both viruses
is largely dependent on IRF-3. Our data suggest that events during or
downstream of viral entry, but prior to viral replication are required
for the activation of IFNα/β-production in mDC.
In paper III, we show that SFV provides an adjuvant effect on antibody
responses against co-administered protein antigens. The adjuvant effect
of SFV is abolished in mice lacking the IFNα/β receptor (IFNR-AR1-/-
mice). In contrast, amplitude, longevity and composition of the antibody
responses directed against virus-encoded antigens are intact in the
absence of IFNα/β-signalling. Antibody responses against both the
virus-encoded antigens and against co-administered antigens are also
intact in MyD88-/- and TLR3-/- mice, in agreement with the observation
that these mice are capable of IFNα/β induction in response to SFV.
Further, we show that rSFV-induced antibody responses are dependent on T
cell help and we suggest that the absence of IFNα/β-signalling in the
IFNR-AR1-/- mice leads to insufficient priming of T helper cells by DC.
These results show that virus-induced IFNα/β can act as a potent adjuvant
for antibody responses against co-administered protein antigens, but that
IFNα/β are not required for the induction of immune responses against
virus-encoded antigens.
In paper IV, we show that CD8+ T cell responses directed against
SFV-encoded antigens are enhanced in the absence of IFNα/β-signalling.
MHC class I tetramer staining demonstrated that the number of
antigen-specific CD8+ T cells is lower both in blood and spleen of
SFV-immunized wildtype mice compared to in SFV-immunized IFN-AR1-/- mice.
The number of IFNγ-producing CD8+ T cells in spleen was also lower in
wildtype mice than in mice lacking the IFN-AR1. Wildtype and IFN-AR1-/-
mice immunized with ex vivo-infected wildtype mouse embryonic fibroblasts
cells gave similar results. These data suggest that IFNα/β signalling
restricts the CD8+ T cell responses to virally encoded antigens, in
contrast to its previously shown enhancing effect on cross-presentation
of protein-based antigens.
List of papers:
I. Hidmark AS, McInerney GM, Nordstrom EK, Douagi I, Werner KM, Liljestrom P, Karlsson Hedestam GB. (2005). "Early alpha/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88." J Virol 79(16): 10376-85
Pubmed
II. Douagi I, McInerney GM, Hidmark AS, Miriallis V, Johansen K, Svensson L, Karlsson Hedestam GB. (2007). "Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts." J Virol. 81(6): 2758-68
Pubmed
III. Hidmark AS, Nordstrom EK, Dosenovic P, Forsell MN, Liljestrom P, Karlsson Hedestam GB. (2006). "Humoral responses against coimmunized protein antigen but not against alphavirus-encoded antigens require alpha/beta interferon signaling." J Virol. 80(14): 7100-10
Pubmed
IV. Hidmark ÅS, Douagi I, Nordström EK, Dosenovic P, Karlsson Hedestam GB. (1970). "CD8+ T cell responses against alphavirus-encoded antigens are enhanced in the absence of IFNá/â signaling." (Submitted)
I. Hidmark AS, McInerney GM, Nordstrom EK, Douagi I, Werner KM, Liljestrom P, Karlsson Hedestam GB. (2005). "Early alpha/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88." J Virol 79(16): 10376-85
Pubmed
II. Douagi I, McInerney GM, Hidmark AS, Miriallis V, Johansen K, Svensson L, Karlsson Hedestam GB. (2007). "Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts." J Virol. 81(6): 2758-68
Pubmed
III. Hidmark AS, Nordstrom EK, Dosenovic P, Forsell MN, Liljestrom P, Karlsson Hedestam GB. (2006). "Humoral responses against coimmunized protein antigen but not against alphavirus-encoded antigens require alpha/beta interferon signaling." J Virol. 80(14): 7100-10
Pubmed
IV. Hidmark ÅS, Douagi I, Nordström EK, Dosenovic P, Karlsson Hedestam GB. (1970). "CD8+ T cell responses against alphavirus-encoded antigens are enhanced in the absence of IFNá/â signaling." (Submitted)
Issue date: 2007-05-11
Rights:
Publication year: 2007
ISBN: 978-91-7357-227-9
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