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CD4 T Cell-Mediated Protection from Lethal Influenza: Perforin and Antibody-Mediated Mechanisms Give a One-Two Punch¹

Trudeau Institute, Saranac Lake, NY 12983

The mechanisms whereby CD4 T cells contribute to the protective response against lethal influenza infection remain poorly characterized. To define the role of CD4 cells in protection against a highly pathogenic strain of influenza, virus-specific TCR transgenic CD4 effectors were generated in vitro and transferred into mice given lethal influenza infection. Primed CD4 effectors conferred protection against lethal infection over a broad range of viral dose. The protection mediated by CD4 effectors did not require IFN- or host T cells, but did result in increased anti-influenza Ab titers compared with untreated controls. Further studies indicated that CD4-mediated protection at high doses of influenza required B cells, and that passive transfer of anti-influenza immune serum was therapeutic in B cell-deficient mice, but only when CD4 effectors were present. Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer protection. Pfn-deficient CD4 effectors were less able to promote survival in intact BALB/c mice and were unable to provide protection in B cell-deficient mice, indicating that Ab-independent protection by CD4 effectors requires Pfn. Therefore, CD4 effectors mediate protection to lethal influenza through at least two mechanisms: Pfn-mediated cytotoxicity early in the response promoted survival independently of Ab production, whereas CD4-driven B cell responses resulted in high titer Abs that neutralized remaining virus.

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 Public Health Service Grants HL-69325, AI-46530, T32-AI49823 (to D.M.B.), F32-AI056962 (to D.M.B.), and Trudeau Institute.

² Address correspondence and reprint requests to Dr. Deborah M. Brown, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: dbrown{at}trudeauinstitute

³ Abbreviations used in this paper: HA, hemagglutinin; NA, neuraminidase; Tg, transgenic; PR8, influenza A/Puerto Rico/8/34; WT, wild type; Pfn, perforin; EIU, egg infectious unit; PA, acid polymerase; NMS, normal mouse serum; CMA, concanamycin A; FasL, Fas ligand; LN, lymph node.

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