Blimp-1-dependent plasma cell differentiation is required for efficient maintenance of murine gammaherpesvirus latency and antiviral antibody responses.
Recent evidence from the study of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus supports a model in which terminal differentiation of B cells to plasma cells leads to virus reactivation. Here we address the role of Blimp-1, the master transcriptional regulator of plasma cell differentiation, in murine gammaherpesvirus 68 (MHV68) latency and reactivation. Blimp-1 expression in infected cells was dispensable for acute virus replication in the lung following intranasal inoculation and in the spleen following intraperitoneal inoculation with MHV68. However, we observed a role for Blimp-1 in both the establishment of latency and reactivation from latency in vivo. Additionally, plasma cell-deficient mice also exhibited a significant defect in the establishment of latency in the spleen, as well as reactivation from latency, similar to mice that lacked Blimp-1 only in MHV68-infected cells. In the absence of plasma cells, MHV68 infection failed to elicit a strong germinal center response and fewer B cells in the germinal center were MHV68 infected. Notably, the absence of a functional Blimp-1 gene only in MHV68-infected cells led to a decrease in both B-cell and CD4(+) T-cell responses during the establishment of latency. Finally, Blimp-1 expression in infected cells played a critical role in the maintenance of both MHV68 latency in the spleen and antibody responses to MHV68. Together, these studies support a model wherein episodic Blimp-1-mediated plasma cell differentiation leads to MHV68 reactivation, which serves to both renew the latency reservoirs and stimulate long-lived plasma cells to secrete virus-specific antibody.
Siegel
Andrea M
AM
Emory Vaccine Center and Department of Microbiology, 1462 Clifton Road, Suite 429, Atlanta, GA 30329, USA.
Rangaswamy
Udaya Shankari
US
Napier
Ruth J
RJ
Speck
Samuel H
SH
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D002454:Cell Differentiation; D002460:Cell Line; D006566:Herpesviridae Infections / Q000821:virology; D051379:Mice; D010950:Plasma Cells / Q000166:cytology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D018144:Rhadinovirus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D013154:Spleen / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000821:virology; D014775:Virus Activation; D017735:Virus Latency / Q000502:physiology*
D000914:Antibodies, Viral; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1