UMMS Affiliation

Department of Pathology; Program in Immunology and Virology

Publication Date

2013-11-05

Document Type

Article

Subjects

Animals; Antibodies, Viral; B-Lymphocytes; Immunoglobulin G; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Polyomavirus; Polyomavirus Infections; T-Lymphocytes

Disciplines

Immunology of Infectious Disease | Immunopathology | Pathology | Virology

Abstract

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.

Rights and Permissions

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.

DOI of Published Version

10.1128/mBio.00812-13

Source

MBio. 2013 Nov 5;4(6):e00812-13. doi: 10.1128/mBio.00812-13. Link to article on publisher's site

Journal/Book/Conference Title

mBio

Related Resources

Link to Article in PubMed

PubMed ID

24194540

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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