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* Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655; and
Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80045
Development of long-term humoral immunity is a major goal of vaccination, but the mechanisms involved in the formation of long-term Ab responses are still being determined. In this study, we identify a previously unknown requirement for MyD88, an adaptor molecule that mediates signals at most TLRs, for the generation of long-term humoral immunity during live virus infection. Polyoma virus-infected MyD88 knockout mice generated strong acute T cell-dependent antiviral IgM and IgG responses and developed germinal centers. Activation-induced cytidine deaminase, an enzyme required for isotype switching and somatic hypermutation, was also induced in germinal center B cells, similar to wild-type mice. However, MyD88 knockout mice failed to develop bone marrow plasma cells and did not maintain long-term serum antiviral Ab responses. The isotype distribution of antiviral IgG responses was also altered; serum IgG2a and IgG2b levels were diminished, whereas IgG1 responses were not affected. The requirement for MyD88 for the formation of long-term humoral immunity to polyoma virus was intrinsic to B cells and was independent of IL-1R and IL-18R, cytokine receptors that also signal through MyD88. Our findings show that MyD88-dependent signaling pathways in B cells are essential for effectively generating long-term Ab responses and implicate a role for TLR in the formation of long-term humoral immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health Grants CA66644, AI49309, AI17672, and AR35506 and Training Grant AI07272.
2 Current address: Inflammation, Wyeth Research, Cambridge, MA 02140.
3 Address correspondence and reprint requests to Dr. Eva Szomolanyi-Tsuda, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail address: eva.szomolanyi-tsuda{at}umassmed.edu
4 Abbreviations used in this paper: AID, activation-induced cytidine deaminase; ASC, Ab-secreting cell; BM, bone marrow; FDC, follicular dendritic cell; GC, germinal center; KO, knockout; PyV, polyoma virus; TD, T cell dependent; TI, T cell independent; PNA, peanut agglutinin.
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