Effect of Human Cytomegalovirus on Expression of MHC Class I-Related Chains A

Abstract

The MHC-encoded MHC class I-related chains A (MICA) glycoproteins are known to enhance the functions of NK and T cells by ligating the stimulating receptor NKG2D and appear to play an important role in host defense. Human CMV (HCMV) evades the immune response in many different ways, but has not previously been found to down-regulate MICA. We have found that a common form of MICA, which has a nucleotide insertion in exon 5 corresponding to the transmembrane region and no cytoplasmic tail, was increased on the surface of fibroblasts HFS-13 compared with the mock-infected sample of the same cells that had been cultured to confluence. However, an astrocytoma cell line, U373, which has a full-length variant of MICA, showed that the expression of MICA was decreased after HCMV infection. Retroviral transduction of different MICA alleles into fibroblasts HFF-D, which express no MICA of their own, established that full-length MICA was down-regulated by HCMV, and the truncated form was not. Fibroblasts with decreased MICA due to HCMV infection were found to be protected from NK cell killing, whereas in the presence of the truncated form of MICA, the virus-infected cells were destroyed. Thus, the truncated form of MICA, which is the most common, has a mutation that allows it to persist on the surface and hinder efforts of the virus to evade the immune response.

Transcriptional regulation of MICA and MICB: A novel polymorphism in MICB promoter alters transcriptional regulation by Sp1

“…MICA and MICB expression is normally restricted to the intestinal epithelium with limited surface expression [12]. In pathological conditions (cancer, infection, hypoxia, heat shock), MICA and MICB expression is inducible by as of yet ill-defined mechanisms [13][14][15]. It is also known that MIC expression is induced in CMV-infected cells and in non-tumor cell lines by DNA damage [13,16].…”

“…In pathological conditions (cancer, infection, hypoxia, heat shock), MICA and MICB expression is inducible by as of yet ill-defined mechanisms [13][14][15]. It is also known that MIC expression is induced in CMV-infected cells and in non-tumor cell lines by DNA damage [13,16]. Upregulation of the expression of MIC genes in response to biological stress is recognized by the NKG2D activating receptors in NK cells, ab T and cd T lymphocytes acting as a mechanism of immunosurveillance [17][18][19].…”

Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity

“…The *008 MICA allele is also resistant to down-regulation by HCMV (8), and it will be important to determine whether viral infection has driven selection for this allele.…”

“…Cell surface MIC expression can be induced by heat shock or infection and signals to the immune system that a cell is stressed or abnormal (6,7). The importance of the NKG2D activatory pathway is highlighted by the down-regulation of its ligands by multiple viruses, including human cytomegalovirus (HCMV) (8,9), mouse CMV (10-13), zoonotic orthopoxviruses (14), and HIV (15).…”

A transmembrane‐anchored rat RAE‐1‐like transcript as a ligand for NKR‐P2, the rat ortholog of human and mouse NKG2D

“…Similarly, viruses have developed clever strategies to subvert the NKG2D-mediated anti-viral NK cell immune response. Both human and mouse cytomegaloviruses, encode proteins that inhibit the activation of NK cells by down-regulating cellular ligands for NKG2D [31][32][33][34][35][36][37], thus demonstrating the importance of this powerful immune surveillance system.…”