title: Interleukin 21 signaling in B cells is required for efficient establishment of murine gammaherpesvirus latency.
abstract: The human gammaherpesviruses take advantage of normal B cell differentiation pathways to establish life-long infection in memory B cells. Murine gammaherpesvirus 68 (MHV68) infection of laboratory strains of mice also leads to life-long infection in memory B cells. To gain access to the memory B cell population, MHV68 infected B cells pass through the germinal center reaction during the onset of latency and require signals from T follicular helper (TFH) cells for proliferation. Interleukin 21 (IL-21), one of the secreted factors produced by TFH cells, plays an important role in both the maintenance of the germinal center response as well as in the generation of long-lived plasma cells. Using IL-21R deficient mice, we show that IL-21 signaling is required for efficient establishment of MHV68 infection. In the absence of IL-21 signaling, fewer infected splenocytes are able to gain access to either the germinal center B cell population or the plasma cell population--the latter being a major site of MHV68 reactivation. Furthermore, the germinal center B cell population in IL-21R(-/-) mice is skewed towards the non-proliferating centrocyte phenotype, resulting in reduced expansion of infected B cells. Additionally, the reduced frequency of infected plasma cells results in a significant reduction in the frequency of splenocytes capable of reactivating virus. This defect in establishment of MHV68 infection is intrinsic to B cells, as MHV68 preferentially establishes infection in IL-21R sufficient B cells in mixed bone marrow chimeric mice. Taken together, these data indicate that IL-21 signaling plays multiple roles during establishment of MHV68 infection, and identify IL-21 as a critical TFH cell-derived factor for efficient establishment of gammaherpesvirus B cell latency.
authors: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Christopher M
authors: CM
authors: Collins
authors: Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Samuel H
authors: SH
authors: Speck
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology*; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018144:Rhadinovirus / Q000502:physiology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D017735:Virus Latency / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21