B Cell-Intrinsic SHP1 Expression Promotes the Gammaherpesvirus-Driven Germinal Center Response and the Establishment of Chronic Infection. J Virol 2019 Dec 12;94(1)
Date
10/11/2019Pubmed ID
31597758Pubmed Central ID
PMC6912115DOI
10.1128/JVI.01232-19Scopus ID
2-s2.0-85076447506 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in the majority of adults worldwide. Chronic gammaherpesvirus infection has been implicated in both lymphomagenesis and, somewhat controversially, autoimmune disease development. Pathogenesis is largely associated with the unique ability of gammaherpesviruses to usurp B cell differentiation, specifically, the germinal center response, to establish long-term latency in memory B cells. The host tyrosine phosphatase SHP1 is known as a brake on immune cell activation and is downregulated in several gammaherpesvirus-driven malignancies. However, here we demonstrate that B cell- but not T cell-intrinsic SHP1 expression supports the gammaherpesvirus-driven germinal center response and the establishment of viral latency. Furthermore, B cell-intrinsic SHP1 deficiency cooperated with gammaherpesvirus infection to increase the levels of double-stranded DNA-reactive antibodies at the peak of viral latency. Thus, in spite of decreased SHP1 levels in gammaherpesvirus-driven B cell lymphomas, B cell-intrinsic SHP1 expression plays a proviral role during the establishment of chronic infection, suggesting that the gammaherpesvirus-SHP1 interaction is more nuanced and is modified by the stage of infection and pathogenesis.IMPORTANCE Gammaherpesviruses establish lifelong infection in a majority of adults worldwide and are associated with a number of malignancies, including B cell lymphomas. These viruses infect naive B cells and manipulate B cell differentiation to achieve a lifelong infection of memory B cells. The germinal center stage of B cell differentiation is important as both an amplifier of the viral latent reservoir and the target of malignant transformation. In this study, we demonstrate that expression of tyrosine phosphatase SHP1, a negative regulator that normally limits the activation and proliferation of hematopoietic cells, enhances the gammaherpesvirus-driven germinal center response and the establishment of chronic infection. The results of this study uncover an intriguing beneficial interaction between gammaherpesviruses that are presumed to profit from B cell activation and a cellular phosphatase that is traditionally perceived to be a negative regulator of the same processes.
Author List
Johnson KE, Lange PT, Jondle CN, Volberding PJ, Lorenz UM, Cui W, Dittel BN, Tarakanova VLAuthor
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Antinuclear
B-Lymphocytes
Chronic Disease
DNA
Female
Germinal Center
Herpesviridae Infections
Host-Pathogen Interactions
Humans
Immunologic Memory
Lymphocyte Activation
Male
Mice
Mice, Transgenic
Primary Cell Culture
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Rhadinovirus
T-Lymphocytes
Tumor Virus Infections
Virus Latency
