Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus

Abstract

The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown. The majority of CD1 molecules are classified on the basis of homology as group 1 CD1 and are present almost exclusively on professional antigen-presenting cells such as dendritic cells, which are a major target for HCMV infection and latency. We have determined that HCMV encodes multiple blocking strategies targeting group 1 CD1 molecules. CD1 transcription is strongly inhibited by the HCMV interleukin-10 homologue cmvIL-10. HCMV also blocks CD1 antigen presentation posttranscriptionally by the inhibition of CD1 localization to the cell surface. This function is not performed by a known HCMV MHC class I-blocking molecule and is substantially stronger than the blockage induced by herpes simplex virus type 1. Antigen presentation by CD1 is important for the development of the antiviral immune response and the generation of mature antigenpresenting cells. HCMV present in antigen-presenting cells thus blunts the immune response by the blockage of CD1 molecules.

Preferential Expansion of Human Virus-Specific Multifunctional Central Memory T Cells by Partial Targeting of the IL-2 Receptor Signaling Pathway: The Key Role of CD4+ T Cells

“…Briefly, monocytes incubated with HCMV-related laboratory wild-type strain NEWT were used as targets (22). In addition, autologous LCL were pulsed with 1 mg/ml overlapping HCMV pp65/IE-1 peptide pools, whereas unpulsed LCL were used as control targets.…”

“…Following reactivation, HCMV early Ags can be presented by circulating monocytes and their derivatives. This can be simulated by infecting monocyte-derived immature dendritic cells (iDC) using HCMV wild-type strain NEWT (22). The lower epitope density on infected cells compared with peptide-loaded cells is a challenge requiring highly effective T cell recognition.…”

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

“…These results may be evidence supporting that immature hCD1d undergoes ubiquitin mediated degradation. Previous report showed that the expression of group 1 CD1 molecules (hCD1a, hCD1b, hCD1c) is down-regulated after HCMV infection (Raftery et al, 2008). Interestingly, these down-regulation of group 1 CD1 molecules is not due to HCMV encoded short glycoproteins (US2, US3, US6, and US11), but the transcriptional inhibition of group 1 CD1 molecules through HCMV IL-10 homologue (Raftery et al, 2008).…”

“…Previous report showed that the expression of group 1 CD1 molecules (hCD1a, hCD1b, hCD1c) is down-regulated after HCMV infection (Raftery et al, 2008). Interestingly, these down-regulation of group 1 CD1 molecules is not due to HCMV encoded short glycoproteins (US2, US3, US6, and US11), but the transcriptional inhibition of group 1 CD1 molecules through HCMV IL-10 homologue (Raftery et al, 2008). However, our results indicated that HCMV US2 interacts with hCD1d through direct protein-protein interaction and leads the proteasomal degradation of hCD1d in an ubiquitin-dependent manner.…”

Subviral Dense Bodies of Human Cytomegalovirus Stimulate Maturation and Activation of Monocyte-Derived Immature Dendritic Cells

“…Monocytederived, immature DC (iDC) are fully permissive to HCMV replication (3), but infection of these cells is restricted to strains expressing the viral genes UL128 to UL131A (4). Infection of iDC by HCMV and its impact on their maturation and function have been studied by several laboratories (5)(6)(7)(8)(9)(10). There is consensus that T cell costimulatory molecules, such as CD40, CD80, and CD86 and MHC classes I and II, are downregulated on the surfaces of iDC following HCMV infection (2).…”