Biology Reference
In-Depth Information
MHC class I. Recent data revealed an astounding variety of methods in triggering or
inhibiting activatory and inhibitory receptors found on NK cells, NKT cells, T cells as
well as auxiliary cells of the immune system. The multitude and complexity of these
mechanisms is fascinating and continues to reveal novel insights into the host-patho-
gen interaction and novel cell biological and immunological concepts.
The Type I Interferon System and Its Effects on CMV Replication
Induction of IFN
Interferons (IFNs) are powerful antimicrobial cytokines that induce the expression
of numerous IFN-stimulated genes (ISGs). The actual antiviral effects are conferred
by ISG products that target different stages of virus replication (Samuel 2001).
CMV replication is susceptible to the effects of ISGs and IFN-induced cellular
states in vitro (Gribaudo et al. 1993; Torigoe et al. 1993; Chin and Cresswell 2001;
Sainz et al. 2005; DeFilippis et al. 2006) and in vivo for murine CMV (MCMV)
(Yeow et al. 1998; Cull et al. 2002; Salazar-Mather et al. 2002).
IFN-dependent ISG transcription is induced by signal transduction triggered by IFNα
or β binding to the type I IFN receptor, resulting in phosphorylation of tyrosine kinase 2
(Tyk2) and Janus kinase 1 (JAK1) that subsequently phosphorylate STAT (signal trans-
ducers and activators of transcription) 2 (Fig. 1). STAT2 phosphorylation leads to its
heterodimerization with STAT1, association with IFN regulatory factor 9 (IRF9), and
nuclear accumulation of the complex (termed IFN-stimulated gene factor 3; ISGF3).
ISGF3 binds to IFN-stimulated response elements (ISREs) contained in the promoters
of numerous ISGs, resulting in their transcriptional upregulation (Shuai and Liu 2003).
Induction of IFNβ itself (reviewed in Hiscott et al. 2003) occurs following stimula-
tion of pattern recognition receptors (PRRs) and involves signaling separate from the
JAK/STAT pathway. PRRs detect molecular components of pathogens such as LPS
and double-stranded RNA (dsRNA). The best-studied PRRs, Toll-like receptors
(TLRs), are expressed predominantly in immune surveillance cells such as DCs and
macrophages (Martin and Wesche 2002; Kawai and Akira 2006). TLR activation
triggers secretion of inflammatory cytokines and expression of co-stimulatory mole-
cules that activate innate and adaptive immune responses (Takeuchi and Akira 2001).
A separate class of cytoplasmic PRRs detects virus-specific molecules and is also
capable of inducing IFNβ (Kato et al. 2005). These include retinoic acid inducible
gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) (Andrejeva
et al. 2004; Yoneyama et al. 2004), which react to dsRNA (Gitlin et al. 2006; Kato et al.
2006). The recently identified receptor DAI also recognizes dsDNA (Takaoka et al.
2007). Two ubiquitous transcription factors, IFN regulatory factor 3 (IRF3) and
nuclear factor kappa B (NFκB), are terminal in the PRR-triggered signaling cascades
and are both required for transcription of the IFNβ gene. Both reside in the cytoplasm
but accumulate in the nucleus upon activation, where they bind to the IFNβ promoter.
IRF3 also induces a subset of ISGs (Wathelet et al. 1998; Hiscott et al. 2003).
