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B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms¹

Trudeau Institute, Saranac Lake, NY 12983

Immunity to heterosubtypic strains of influenza is thought to be mediated primarily by memory T cells, which recognize epitopes in conserved proteins. However, the involvement of B cells in this process is controversial. We show in this study that influenza-specific memory T cells are insufficient to protect mice against a lethal challenge with a virulent strain of influenza in the absence of B cells. B cells contribute to protection in multiple ways. First, although non-neutralizing Abs by themselves do not provide any protection to challenge infection, they do reduce weight loss, lower viral titers, and promote recovery of mice challenged with a virulent heterosubtypic virus in the presence of memory T cells. Non-neutralizing Abs also facilitate the expansion of responding memory CD8 T cells. Furthermore, in cooperation with memory T cells, naive B cells also promote recovery from infection with a virulent heterosubtypic virus by generating new neutralizing Abs. These data demonstrate that B cells use multiple mechanisms to promote resistance to heterosubtypic strains of influenza and suggest that vaccines that elicit both memory T cells and Abs to conserved epitopes of influenza may be an effective defense against a wide range of influenza serotypes.

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 work was supported by Trudeau Institute and National Institutes of Health Grants AI072689, AI61511, and HL69409 (to T.D.R.), and AI68056 and AI50844 (to F.E.L.). R.S.M. was supported by National Institutes of Health Training Grant AI49823.

² Address correspondence and reprint requests to Dr. Troy Randall, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: trandall{at}trudeauinstitute.org

³ Abbreviations used in this paper: HA, hemagglutinin; NA, neuraminidase; NP, nucleoprotein; M, matrix; µMT, B6.129S2-Igh-6^tm1Cgn/J; PA, acidic polymerase; PB, basic polymerase; M2e, external domain of M2; EIU, egg infectious units.

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