Abstract
DCs very potently activate CD8+ T cells specific for viral peptides bound to MHC class I molecules. However, many viruses have evolved immune evasion mechanisms, which inactivate infected DCs and might reduce priming of T cells. Then MHC class I cross-presentation of exogenous viral Ag by non-infected DCs may become crucial to assure CD8+ T cell responses. Although many vital functions of infected DCs are inhibited in vitro by many different viruses, the contributions of cross-presentation to T cell immunity when confronted with viral immune inactivation in vivo has not been demonstrated up to now, and remains controversial. Here we show that priming of Herpes Simplex Virus (HSV)-, but not murine cytomegalovirus (mCMV)-specific CD8+ T cells was severely reduced in mice with a DC-specific cross-presentation deficiency. In contrast, while CD8+ T cell responses to mutant HSV, which lacks crucial inhibitory genes, also depended on CD8α+ DCs, they were independent of cross-presentation. Therefore HSV-specific CTL-responses entirely depend on the CD8α+ DC subset, which present via direct or cross-presentation mechanisms depending on the immune evasion equipment of virus. Our data establish the contribution of cross-presentation to counteract viral immune evasion mechanisms in some, but not all viruses.
Highlights
Many viruses utilize a diversity of mechanisms to evade the immune system (Tortorella et al, 2000; Yewdell and Hill, 2002).Especially herpesviruses are extremely potent immune evaders and Herpes Simplex Virus (HSV) shuts down host cell transcription, RNA splicing, and protein synthesis by expressing an arsenal of viral proteins (Hardy and Sandri-Goldin, 1994; Hill et al, 1995; Spencer et al, 1997; Song et al, 2001; Smiley, 2004)
We demonstrate that CD8 T cell responses to all wt and mutant viruses studied depend on CD8α+ DCs, which perform
The virion host shutoff protein encoded by the gene UL41 causes destabilization and degradation of infected host cell mRNAs and is among other effects responsible for down regulation of MHC I synthesis and expression (Hill et al, 1994; Tigges et al, 1996; Hinkley et al, 2000; Koppers-Lalic et al, 2001)
Summary
Many viruses utilize a diversity of mechanisms to evade the immune system (Tortorella et al, 2000; Yewdell and Hill, 2002).Especially herpesviruses are extremely potent immune evaders and Herpes Simplex Virus (HSV) shuts down host cell transcription, RNA splicing, and protein synthesis by expressing an arsenal of viral proteins (Hardy and Sandri-Goldin, 1994; Hill et al, 1995; Spencer et al, 1997; Song et al, 2001; Smiley, 2004). HSV-infected DCs are non-functional and cannot efficiently prime naive T cells in vitro (Salio et al., 1999; Kruse et al, 2000). It has been speculated that non-infected fully functional bystander DCs could cross-present exogenous viral Ag derived from infected and dying cells to secure priming of virusspecific CD8+ T cells (Heath and Carbone, 2001; Jirmo et al., 2009). The selective capacity of CD8α+ DCs to take up dead cells (Iyoda et al, 2002) and to cross-prime CD8 T cells (den Haan et al, 2000) suggests, that this DC subset may be especially important in anti-viral immunity. Several studies have found CD8α+ DCs to present viral Ag to CD8 T cells, when mice were infected with HSV-1, lymphocytic choriomeningitis virus, vaccinia virus, influenza virus, or respiratory syncytial virus (Allan et al, 2003; Smith et al, 2003; Belz et al, 2004a,b, 2005; Bedoui et al, 2009; Jirmo et al, 2009; Lukens et al, 2009) and ablation of CD8α+ DCs in Batf-3-deficient mice abrogated T cell responses to west nile virus completely (Hildner et al, 2008)
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