Viral inhibition of MHC class II antigen presentation

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Abstract

CD4+ T cells can recognize antigens expressed in virus-infected cells and act cytolytically, to produce antiviral cytokines or to co-ordinate antiviral immune responses. Viruses escape detection by CD4+ T cells by at least two mechanisms. First, and perhaps foremost, viruses inhibit induction of the expression of MHC class II genes by blocking interferon-γ (IFN-γ) signal transduction and expression of the MHC class II transactivator (CIITA). Second, viruses inhibit the MHC class II antigen presentation pathway by affecting the stability or intracellular sorting of class II proteins. It appears that this viral inhibition is designed to prevent presentation of endogenous viral antigens in virus-infected host cells, rather than presentation of exogenous antigens in ‘professional’ antigen-presenting cells.

Section snippets

Transcription of MHC class II genes and induction by IFN-γ

The human class II proteins DP, DQ, DR, DM and DO are encoded in the MHC region on chromosome 6. The class II-associated invariant chain (Ii) and class II transactivator (CIITA) genes are encoded outside the MHC locus on chromosomes 5 and 16, respectively. The transcription of class II genes, including that of Ii, is largely or entirely dependent on the expression of CIITA, and class II and CIITA proteins are constitutively expressed by thymic epithelial cells, activated T cells and

Inhibition of IFN-γ-induced MHC class II expression by viruses

Every step in the IFN-γ signal transduction pathway leading to induction of CIITA and class II gene expression is inhibited by one virus or another (Table 1). Given the impact of IFN-γ on most phases of virus replication, it is probable that all or most virus families inhibit IFN-γ signaling. This reduces not only expression of class II genes but also expression of numerous other antiviral IFN-induced genes. Often, it is not clear whether the effects described here are specifically designed to

MHC class II antigen presentation pathway

Several viruses also target the proteins that participate in the MHC class II antigen presentation pathway. At present, there are fewer examples of viral inhibition of class II proteins compared with those involving inhibition of class II gene expression. However, the viral proteins that do affect class II presentation have provided new insights into how this pathway functions. The MHC class II pathway is described in detail in Figure 2. MHC class II αβ dimers assemble with Ii in the

Viral inhibition of MHC class II antigen presentation

Several early studies were consistent with the notion that viruses might inhibit class II antigen presentation to CD4+ T cells but it was not always clear whether the effects were pleiotropic or specific to class II proteins. The product of an influenza hemagglutinin minigene expressed by a vaccinia virus vector was presented by B cells to class I-restricted CD8+ T cells but not to class II-restricted CD4+ T cells 25, 26. The corresponding peptide was presented to class II-restricted CD4+ T

Viral inhibition of endogenous, rather than exogenous, class II-mediated antigen presentation

At least three different families of viruses – herpes, retro and pox – obstruct the class II pathway. The viral proteins responsible for this inhibition are expressed only within virus-infected cells and are not obviously elicited exogenously to other cells. How these viruses benefit from inhibiting class II antigen presentation is an interesting concept. Most illustrations of the class II pathway show extracellular antigens taken up by endocytosis or phagocytosis into professional APCs

Viral inhibition of class II presentation by expression of interleukin-10 (IL-10)

Certain viruses inhibit the class II pathway by inducing cellular IL-10 or by expressing a viral homolog of IL-10 that can decrease cell-surface MHC class II (Table 2) (reviewed in Refs 56, 57). The viral and cellular IL-10 molecules apparently increase the pH of the MIIC, inhibiting the activity of cathepsins, thereby reducing the generation of antigenic peptides [58]. The net effect is reduced movement of class II complexes from the MIIC to the cell surface [59]. In contrast to the effects of

Conclusion

CD4+ T cells have a crucial role in antiviral immune responses. Viruses block the induction of class II genes in host cells, and impede the loading of peptides derived from viral proteins onto class II proteins. These effects appear to be largely aimed at preventing class II-mediated presentation of endogenous viral antigens produced within infected cells. The most common form of inhibition and the first line of defense involves interrupting the IFN-γ–Jak–STAT signal transduction pathway that

Acknowledgements

We thank Curt Horvath, Philippe Benaroch, Joanne Trgovcich, Daniel Sedmak and John Trowsdale for critical input to this manuscript. We are grateful to Tiffani Howard for the artwork. We apologize to those whose original work could not be cited due to space limitations. Our own work was supported by NIH grants EY11245 and CA73996.

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