Altered MicroRNA Expression after Infection with Human Cytomegalovirus Leads to TIMP3 Downregulation and Increased Shedding of Metalloprotease Substrates, Including MICA

Abstract

Proteolytic shedding of ligands for the NK group 2D (NKG2D) receptor is a strategy used by tumors to modulate immune recognition by NK cells and cytotoxic T cells. A number of metalloproteases, especially those of the a disintegrin and metalloprotease (ADAM) family, can mediate NKG2D ligand cleavage and this process can be modulated by expression of the thiol isomerase ERp5. In this article, we describe that an increased shedding of the NKG2D ligand MICA is observed postinfection with several strains of human CMV due to an enhanced activity of ADAM17 (TNF-α converting enzyme) and matrix metalloprotease 14 caused by a reduction in the expression of the endogenous inhibitor of metalloproteases tissue inhibitors of metalloproteinase 3 (TIMP3). This decrease in TIMP3 expression correlates with increased expression of a cellular miRNA known to target TIMP3, and we also identify a human CMV–encoded microRNA able to modulate TIMP3 expression. These observations characterize a novel viral strategy to influence the shedding of cell-surface molecules involved in immune response modulation. They also provide an explanation for previous reports of increased levels of various ADAM17 substrates in the serum from patients with CMV disease. Consistent with this hypothesis, we detected soluble MICA in serum of transplant recipients with CMV disease. Finally, these data suggest that it might be worthwhile to prospectively study ADAM17 activity in a larger group of patients to assay whether this might be a useful biomarker to identify patients at risk for development of CMV disease.

A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

“…However, circulating sMICA might also derive from PBMC shedding. As an example, the family of herpesviridae, whose ability to trigger lupus initiation and exacerbation is widely recognized, displays an array of MICA-targeted immune evasion strategies which not only involve shedding, but also transcriptional suppression and early degradation of the molecule [24,25]. In our patients, mRNA levels in B lymphocytes changed in the opposite direction to sMICA and to the amount of proteinuria.…”

“…In spite of the scant number of patients with active LN at enrolment these findings may warrant further research, as they could point to immune escape as a mechanism accounting for the impairment of NK functions in patients with LN [23]. As an example, the family of herpesviridae, whose ability to trigger lupus initiation and exacerbation is widely recognized, displays an array of MICA-targeted immune evasion strategies which not only involve shedding, but also transcriptional suppression and early degradation of the molecule [24,25].…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…Recent data in CMV‐infected human cells showed that UL148‐induced down‐regulation of CD58 (a cell surface molecule important for co‐stimulation of effector T cells) leads to dampening of a productive immune response, which includes loss of cytotoxic activity by cytotoxic lymphocytes and natural killer cells . This may be augmented with down‐regulation of APM‐associated components to subdue the immune response . This may represent a general mechanism of immune suppression employed by CMV which may also be relevant to cancer.…”

“…142 This may be augmented with down-regulation of APM-associated components to subdue the immune response. 143,144 This may represent a general mechanism of immune suppression employed by CMV which may also be relevant to cancer. In contrast to data obtained from patients with GBM, several reports showed anergy of tumour-specific T cells in patients with melanoma, whereas CMV-specific T cells in the same patients were functional.…”

A short half‐life of ULBP1 at the cell surface due to internalization and proteosomal degradation

“…Since the expression of stress‐inducible NKG2D‐L at the surface of a putative target cell leads to its lysis, regulation of their expression is crucial for cell survival. Mechanisms to control surface expression of NKG2D‐L include all levels of regulation (for review: 13 , 14 ): transcriptional , in response to different types of stress, such as DNA damage, 15 heat shock 10 or proteasome inhibition; 16 , 17 post‐transcriptional , including miRNA‐mediated regulation 18 , 19 , 20 ; and post‐translational levels of regulation of which the best characterized is the release of these molecules either as shed, soluble species, after proteolytic cleavage mediated by metalloproteinases, 21 , 22 , 23 or in exosomes 23 , 24 (reviewed in Fernandez‐Messina et al 25 ).…”