Human Cytomegalovirus Inhibits Differentiation of Monocytes into Dendritic Cells with the Consequence of Depressed Immunological Functions

Abstract

Human cytomegalovirus (HCMV) infections in immunocompromised patients are associated with impaired immunological functions. Blood monocytes, which can differentiate into dendritic cells upon cytokine stimulation, play a central role in adequate immune reactivity and are believed to carry latent HCMV. We demonstrate here that HCMV infection of monocytes results in a block in the cytokine-induced differentiation of monocytes into functionally active CD1a-positive dendritic cells, which exhibited severely depressed immunological functions in vitro. The HCMV-infected cells exhibited a significantly reduced ability to endocytose fluorescein isothiocyanate-labeled dextran particles as well as a more than 90% reduced ability to migrate in response to the chemoattractant factors RANTES, MIP-1␣, and MIP-3␤. Interestingly, HCMV-infected cells expressed high levels of the costimulatory molecule CD86, in contrast to the low levels of expression that was observed on uninfected monocytes and uninfected immature dendritic cells. Furthermore, HCMV-infected CD1a-negative cells were unable to induce a T-cell response. Thus, these observations suggest that HCMV infection of monocytes in vitro blocks cytokine-induced dendritic cell differentiation, and since dendritic cells play a central role in initiating immune responses, these findings suggest a powerful tactic to avoid immune recognition and to blunt the immune response at early phases of infection.

Human Cytomegalovirus Alters Localization of MHC Class II and Dendrite Morphology in Mature Langerhans Cells

“…Notably, HCMV directly infects professional APC, including monocytes (6), macrophages (7), and dendritic cells (DCs) (8 -10). In addition, myeloid lineage precursors of these cells provide an important site for HCMV latency (11,12), and reactivation of viral replication is thought to be associated with differentiation of precursors into APCs (13).…”

Impaired Direct Priming of CD8 T Cells by Donor-Derived Cytomegalovirus Following Kidney Transplantation

“…This novel finding with regard to transplantation-associated viral transmission resonates with data from models of murine CMV, suggesting cross-presentation as the primary pathway to antiviral immunity, [16][17][18] with direct priming inhibited due to CMV-mediated downregulation of activating co-stimulatory molecules (such as CD86) and upregulation of inhibitory ligands (such as PD-L1) on APCs, [19][20][21] along with inhibition of dendritic cell maturation and antigen presentation. 22,23 Absence of directly primed CD8+ T cell immune responses raises questions regarding how infection is ultimately controlled within donor tissue. Several possibilities include CD4+ T cell immunity, natural killer cells, and humoral immunity.…”

Role of cytomegalovirus on the maturation and function of monocyte derived dendritic cells of liver transplant patients

“…DCs have superiority over other APCs in viral infections to stimulate T-cell responses and maintaining protective antiviral immunity [15] . DCs are critical initiators of cellular immunity against viruses especially CMV [1] .…”

“…DCs are determinative initiators of cellular immunity against CMV infection [1] . DCs also act with superiority over other antigen-presenting cells (APCs) in stimulating T-lymphocyte responses and maintaining protective antiviral immunity [15] . CMV can interfere with maturation and antigenpresenting function of DCs and also disturb both innate and adaptive immunity [14,16] .…”