Roles of CD4⁺T-Cell-Independent and -Dependent Antibody Responses in the Control of Influenza Virus Infection: Evidence for Noncognate CD4⁺T-Cell Activities That Enhance the Therapeutic Activity of Antiviral Antibodies

Abstract

Previous studies have indicated that B cells make a significant contribution to the resolution of influenza virus infection. To determine how B cells participate in the control of the infection, we transferred intact, major histocompatibility complex class II (MHC-II)-negative or B-cell receptor (BCR)-transgenic spleen cells into B-celldeficient and CD8؉ T-cell-depleted MT mice, termed MT(؊8), and tested them for ability to recover from infection. MT(؊8) mice that received no spleen cells invariably succumbed to the infection within 20 days, indicating that CD4 ؉ T-cell activities had no significant therapeutic activity on their own; in fact, they were harmful and decreased survival time. Interestingly, however, they became beneficial in the presence of antiviral antibody (Ab). Injection of MHC-II (؊/؊) spleen cells, which can provide CD4 ؉ T-cell-independent (TI) but not T-celldependent (TD) activities, delayed mortality but only rarely resulted in clearance of the infection. By contrast, 80% of MT(؊8) mice injected with normal spleen cells survived and resolved the infection. Transfer of BCR-transgenic spleen cells, which contained ϳ10 times fewer virus-specific precursor B cells than normal spleen cells, had no significant impact on the course of the infection. Taken together, the results suggest that B cells contribute to the control of the infection mainly through production of virus-specific Abs and that the TD Ab response is therapeutically more effective than the TI response. In addition, CD4؉ T cells appear to contribute, apart from promoting the TD Ab response, by improving the therapeutic activity of Ab-mediated effector mechanisms.

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

“…A recent report from Mozdzanowska et al (49) group also demonstrated that the efficacy of passive Ab transfer was enhanced in the presence of endogenous CD4 cells in a primary response to influenza. In that study, highly purified mAb was injected before infection, and several times thereafter, to promote survival, but the contribution of the CD4 component was not elucidated.…”

Adjuvant solution for pandemic influenza vaccine production

“…This relationship was observed by modifying the vaccine with more antigen or using GLA-SE, and by comparing responses between mouse strains where C57BL/6 mice expressed detectable day 14 antibody titers at lower antigen doses and recovered faster from virus than BALB/c mice. Undoubtedly, CD4 helper T cells are critical in this regard because depletion of this lineage during rH5 priming eliminated antibody production and prevented survival (25,26). Protection may also have been influenced by the induction of cytotoxic CD4 T cells or after CD4-mediated help of killer CD8 T cells (27), although antigen-specific CD8 T cells were not observed in peptide stimulated splenocytes before challenge.…”

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

“…B cell responses importantly contribute to survival from both primary as well as secondary infection with influenza virus (1)(2)(3)(4)(5)(6)(7). Consistent with their role during primary infection, B cell responses in the local draining lymph nodes of the respiratory tract (mediastinal lymph nodes (MLN) 3 ) are induced within 48 -72 h after infection (8), thus around the time of peak lung viral loads.…”