Abstract
Human cytomegalovirus (CMV) exerts diverse and complex effects on the immune system, not all of which have been attributed to viral genes. Acute CMV infection results in transient restrictions in T cell proliferative ability, which can impair the control of the virus and increase the risk of secondary infections in patients with weakened or immature immune systems. In a search for new immunomodulatory proteins, we investigated the UL11 protein, a member of the CMV RL11 family. This protein family is defined by the RL11 domain, which has homology to immunoglobulin domains and adenoviral immunomodulatory proteins. We show that pUL11 is expressed on the cell surface and induces intercellular interactions with leukocytes. This was demonstrated to be due to the interaction of pUL11 with the receptor tyrosine phosphatase CD45, identified by mass spectrometry analysis of pUL11-associated proteins. CD45 expression is sufficient to mediate the interaction with pUL11 and is required for pUL11 binding to T cells, indicating that pUL11 is a specific CD45 ligand. CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off. In the presence of pUL11, several CD45-mediated functions were inhibited. The induction of tyrosine phosphorylation of multiple signaling proteins upon TCR stimulation was reduced and T cell proliferation was impaired. We therefore conclude that pUL11 has immunosuppressive properties, and that disruption of T cell function via inhibition of CD45 is a previously unknown immunomodulatory strategy of CMV.
Highlights
Infection of immunocompetent individuals with human cytomegalovirus (CMV) rarely results in symptomatic disease
We show that a CMV protein, pUL11, which is expressed on the surface of cells, binds to leukocytes by interacting with the receptor tyrosine phosphatase CD45
In T cells, CD45 is essential for transmission of activating signals received via the T cell receptor (TCR) to downstream effector molecules that lead to activation and proliferation of these immune cells
Summary
Infection of immunocompetent individuals with human cytomegalovirus (CMV) rarely results in symptomatic disease. Despite the induction of strong cellular immune responses and neutralizing antibodies, CMV is able to establish a latent infection, and reactivation as well as reinfection with multiple CMV strains seems to be quite frequent [4,5,6]. These properties of CMV have been ascribed to the expression of a series of viral immunomodulatory proteins [3,7]. In individuals with weakened or immature immune systems the balance between host immune control and viral immunomodulation can be shifted in favor of viral replication, resulting in viremia and end-organ disease associated with morbidity and even mortality in CMV-infected transplant recipients, AIDS patients or children congenitally infected with CMV [8]
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