Trends in Immunology
Viral inhibition of MHC class II antigen presentation
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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2016, Current Opinion in ImmunologyDynamic range of Nef-mediated evasion of HLA class II-restricted immune responses in early HIV-1 infection
2015, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Nef exhibits multiple immune evasion functions, including down-regulation of HLA-DR [10] and up-regulation of the invariant chain associated with immature HLA-II (Ii) from the surface of HIV-1-infected cells [11], as well as down-regulation of HLA class I (HLA-I) [12,13]. It is thought that down-regulation of HLA-DR and up-regulation of Ii can subvert HLA-II-restricted antigen presentation and thus antigen-specific CD4+ T cell stimulation [14,15], while down-regulation of HLA-I can subvert HLA-I-restricted CTL responses [12]. The stable expression of Ii prevents peptide binding to mature HLA-II [16], and immature HLA-II associated with Ii on the cell surface is nonfunctional in stimulating CD4+ T cells [17].