Long-lasting T cell-independent IgG responses require MyD88-mediated pathways and are maintained by high levels of virus persistence
Document Type
Journal ArticlePublication Date
2013-11-05Keywords
AnimalsAntibodies, Viral
B-Lymphocytes
Immunoglobulin G
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88
Polyomavirus
Polyomavirus Infections
T-Lymphocytes
Immunology of Infectious Disease
Immunopathology
Pathology
Virology
Metadata
Show full item recordAbstract
Many viruses induce acute T cell-independent (TI) B cell responses due to their repetitive epitopes and the induction of innate cytokines. Nevertheless, T cell help is thought necessary for the development of long-lasting antiviral antibody responses in the form of long-lived plasma cells and memory B cells. We found that T cell-deficient (T cell receptor beta and delta chain [TCRbetadelta] knockout [KO]) mice persistently infected with polyomavirus (PyV) had long-lasting antiviral serum IgG, and we questioned whether they could generate TI B cell memory. TCRbetadelta KO mice did not form germinal centers after PyV infection, lacked long-lived IgG-secreting plasma cells in bone marrow, and did not have detectable memory B cell responses. Mice deficient in CD4(+) T cells had a lower persisting virus load than TCRbetadelta KO mice, and these mice had short-lived antiviral IgG responses, suggesting that a high virus load is required to activate naive B cells continuously, and maintain the long-lasting serum IgG levels. Developing B cells in bone marrow encounter high levels of viral antigens, which can cross-link both their B cell receptor (BCR) and Toll-like receptors (TLRs), and this dual engagement may lead to a loss of their tolerance. Consistent with this hypothesis, antiviral serum IgG levels were greatly diminished in TCRbetadelta KO/MyD88(-/-) mice. We conclude that high persisting antigen levels and innate signaling can lead to the maintenance of long-lasting IgG responses even in the absence of T cell help. IMPORTANCE: Lifelong control of persistent virus infections is essential for host survival. Several members of the polyomavirus family are prevalent in humans, persisting at low levels in most people without clinical manifestations, but causing rare morbidity/mortality in the severely immune compromised. Studying the multiple mechanisms that control viral persistence in a mouse model, we previously found that murine polyomavirus (PyV) induces protective T cell-independent (TI) antiviral IgG. TI antibody (Ab) responses are usually short-lived, but T cell-deficient PyV-infected mice can live for many months. This study investigates how protective IgG is maintained under these circumstances and shows that these mice lack both forms of B cell memory, but they still have sustained antiviral IgG responses if they have high levels of persisting virus and intact MyD88-mediated pathways. These requirements may ensure life-saving protection against pathogens even in the absence of T cells, but they prevent the continuous generation of TI IgG against harmless antigens.Source
MBio. 2013 Nov 5;4(6):e00812-13. doi: 10.1128/mBio.00812-13. Link to article on publisher's siteDOI
10.1128/mBio.00812-13Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43099PubMed ID
24194540Related Resources
Link to Article in PubMedRights
Copyright © 2013 Raval et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
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http://creativecommons.org/licenses/by-nc-sa/3.0/ae974a485f413a2113503eed53cd6c53
10.1128/mBio.00812-13
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Except where otherwise noted, this item's license is described as <p>Copyright © 2013 Raval et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.</p>