Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-alpha and DM-alpha. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.

Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity

“…In case of MHC class Ia or class II, HCMV US2 physically interacts and with heavy chain of MHC molecules and destabilize them (Tomazin et al, 1999;Wiertz et al, 1996). To investigate whether HCMV US2 also destabilizes hCD1d, we tested the stability of hCD1d protein in HCMV US2 overexpressing CD1d.C1R cells (US2), compared with that of empty vector transfectants (Mock) following treatment with cycloheximide.…”

“…Particularly, human cytomegalovirus (HCMV) encodes unique short glycoproteins (US2, US3, US6, US11) expressed during the certain stages of the HCMV infection to avoid immune responses (Pinto and Hill, 2005;Ploegh, 1998;Seriger et al, 2006). These unique short glycoproteins inhibit the antigen presenting ability of major histocompatibility complex (MHC) class Ia and class II which leads to the down-regulation of T cell activity (Tomazin et al, 1999;Wiertz et al, 1996).…”

“…Among several glycoproteins derived from HCMV, US2 can make direct interactions with MHC class Ia or MHC class II molecules (HLA-DM and HLA-DR) and this interaction induces the translocation of MHC class Ia heavy chain or MHC class II α chain from endoplasmic reticulum (ER) to cytoplasm (Tomazin et al, 1999;Wiertz et al, 1996). Consequently, dislocated MHC molecules from ER to cytoplasm are degraded by ubiquitin-dependent proteasome complex (Tomazin et al, 1999;Wiertz et al, 1996).…”

“…Consequently, dislocated MHC molecules from ER to cytoplasm are degraded by ubiquitin-dependent proteasome complex (Tomazin et al, 1999;Wiertz et al, 1996). The degradation of MHC class Ia or class II molecules leads to inhibit antigen presenting mechanism.…”

“…However, not many studies have shown the viral influence on the regulation of iNKT cell activity during infection. In particular, HCMV US2 is well known for modulation of host immunity by down-regulation of MHC class Ia and class II molecules (Tomazin et al, 1999;Wiertz et al, 1996); it is worthwhile to exam the effect of HCMV US2 on the expression or the antigen presenting function of human CD1d (hCD1d) molecule, which present glycolipid antigens to iNKT cells.…”