The Human Cytomegalovirus UL11 Protein Interacts with the Receptor Tyrosine Phosphatase CD45, Resulting in Functional Paralysis of T Cells

PLoS Pathogens

Roland Jacobs¹  Reinhard Schwinzer²  Claudia Pokoyski²  Andreas Pich³  Ildar Gabaev⁴  Lars Steinbrück⁴  Martin Messerle⁴  Thomas F. Schulz⁴  Penelope C. Kay-Fedorov⁴  Richard J. Stanton⁵ 

[1] Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany;Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany;Institute of Toxicology, Hannover Medical School, Hannover, Germany;Institute of Virology, Hannover Medical School, Hannover, Germany;Section of Medical Microbiology, School of Medicine, Cardiff University, Cardiff, United Kingdom

关键词: T cells;    Immune system proteins;    293T cells;    T cell receptors;    TCR signaling cascade;    Cell binding;    Protein interactions;    Flow cytometry;   

DOI  :  10.1371/journal.ppat.1002432

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY