The human immune system can cover the presentation of a wide breadth of pathogen derived antigenic peptides owing to the three extraordinary polymorphic MHC-I genes loci each individual possesses. MHC-I molecules are expressed on the cell surface to communicate primarily with cytotoxic lymphocytes. While mainly the highly polymorphic classical MHC-I (HLA-A/B/C) present endogenous peptides to surveilling CD8+ T-cells, all MHC-I, including non-classical HLA-E/F/G, are able to interact with various inhibitory and/or activating NK cell receptors (NKR).
The unique infection biology of cytomegaloviruses has come along with the evolution of a large array of highly specialized immune evasive genes and reprogramming of multiple immune functions without compromising the human host . HCMV controls distinct checkpoints of the MHC-I antigen presentation pathway by at least five gene products: US2 and US11 degrade MHC-I, US3 retains MHC-I inside the cells and US6 blocks the function of the peptide transporter TAP . In addition, the viral miRNA miR-UL112-5p reduces the expression of ERAP1, a peptide trimming enzyme . Thus, the control of CD8+ T-cell activation through manipulation of classical MHC-I is established and broadly documented. However, how HCMV might interfere with the MHC-I/NKR axis is not well understood.
Interestingly, a highly ADCC reactive NK cell population, also called memory-like NK cells (NKG2Cbright), has been found to expand uniquely in HCMV positive individuals [4, 5]. This NK cell subset exhibit a polarized KIR (killer cell immunoglobulin-like receptor) profile, with prominent expression of self-specific KIRs . Expansion of memory-like NK cells in in vitro co-cultures with HCMV infected fibroblasts revealed an absolute dependency on HLA-E expression . HLA-E is stabilized by MHC-I signal peptides (VL9) and engages in addition to the activating CD94/NKG2C NK cell receptor the inhibitory counterpart CD94/NKG2A. Two HCMV encoded proteins are known to affect HLA-E expression: since US6 blocks TAP function it deprives VL9 ligands from the ER, whereas UL40, which has pirated the VL9 peptide sequence into its signal peptide, loads HLA-E in a TAP-independent manner, i.e. in the presence of US6. Furthermore, we found that the glycoprotein US10 modulates HLA-E expression in HCMV infection.
In this project we will study the concerted molecular manipulation of HLA-E by known HCMV encoded immunoevasins and novel regulators and their effect on immune cell recognition of infected cells.
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