Abstract
Human cytomegalovirus (HCMV) encodes numerous immunomodulatory genes that facilitate its persistence. Previously described mechanisms by which HCMV avoids T cell control typically involve evasion of detection by infected cells. Here, we show that the virus also inhibits T cells directly via an interaction between the pUL11 glycoprotein on infected cells and the CD45 phosphatase on T cells. The antiviral functions of CD4 T cells are impaired as a result of this interaction, largely via induced interleukin 10 (IL-10) secretion in the CD4 T cell central memory compartment, resulting in enhanced viral spread. This establishes CD45 as an inhibitory receptor that regulates antiviral T cell functions and has parallels with the manipulation of natural killer (NK) cells by HCMV. By coculturing donor T cells with HCMV-infected epithelial cells, we observed that CD4 T cells can respond to epithelial cell antigen presentation and can control HCMV spread via cytolytic and cytokine-dependent mechanisms. pUL11 impairs both mechanisms. We showed that pUL11-induced IL-10 secretion requires IL-2, mTOR, and T cell receptor signaling. This characterization of the effects of the pUL11-CD45 interaction may allow for the development of new antiviral therapies and treatments for inflammatory disorders. IMPORTANCE Human cytomegalovirus (HCMV) is adept at avoiding its host's immune defenses, both by evading detection and by directly inhibiting immune cells. This can lead to a loss of control of the infection, and dangerous disease can result, particularly in cases in which an individual's immune system is immature, weak, or suppressed. T cells form a crucial part of the response to HCMV and are used in cellular HCMV therapies. We show that an interaction between a viral glycoprotein (pUL11) and a T cell surface receptor (CD45) impairs T cell memory functions and allows for increased viral spread. This defines a new immunomodulatory strategy for the virus as well as a new T cell regulatory mechanism. These results are important, as they increase our understanding of how T cells function and how HCMV disrupts them. This will allow for the development of new antiviral therapies that restore T cell functions and indicates a new target for controlling pathological T cell disorders.