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

Many components of the innate and adaptive defense contribute to the control of an influenza virus infection in the immunologically intact mouse. This has been evidenced by increased morbidity and mortality or delayed recovery of mice that have a defective alpha/beta interferon (IFN-α/β) response system (17, 22, 36) or complement system (25, 31) or are deficient in major histocompatibility complex class I (MHC-I)-restricted CD8+ T (7) or B (3, 18, 21, 32, 59, 62) cells. Similarly, modifications that decrease the susceptibility of the virus to innate inhibitors in body fluids (52), cellular defense systems induced by IFNs and tumor necrosis factor alpha (TNF-α) (8, 55, 61), or recognition by CD8+ T cells (62) typically increase viral pathogenicity. However, although an intact multipronged defense is important for recovery from a very severe infection, there is substantial redundancy in the antiviral defense, and no known defense mechanism is absolutely required for effective control of an influenza virus infection of low to moderate severity. Thus, mice lacking IFN-α/β receptors (51) or CD8+ T (12, 14, 43, 59), CD4+ T (9, 14, 46), or B (14, 53) cells are all capable of resolving an infection of moderate severity with no or minimal delay. The relative importance of the various defense activities in the control of the infection in the intact host is not entirely resolved, as no single influenza virus strain has been tested systematically with the same challenge and readout method in the various murine knockout models. Nevertheless, the fact that the 50% lethal doses (LD50s) of three distinct virus strains—the highly pathogenic A/PR/8/34 (H1N1) (18) and A/Japan/305 (H2N2) (21) and the minimally pathogenic plasmid-generated H3N2 reassortant HK-RG (62) strains—were decreased ≥10-fold in B-cell-deficient compared to intact mice provides strong support for the notion that B cells make an important contribution to the control of the primary infection in the intact mouse, although additional defects in B-cell-deficient mice, such as the poor development of splenic T-cell zones and reduced splenic T-cell numbers (47) and possible defects in airway-associated lymphoid tissues (19) and in CD4+ T cells (4, 39), may also contribute to their low resistance to influenza virus infection. A significant role of B cells in the resolution of the infection is consistent also with the kinetics of the primary antibody (Ab) response, whose rise coincides with virus clearance (15, 24, 34, 58). The aim of this study was to determine how B cells contribute to the control of the infection. B cells may participate through several activities, including (i) production of virus-specific Abs, in both T-independent (TI) and T-dependent (TD) fashion; (ii) secretion of cytokines/chemokines with antiviral and/or immunostimulatory activities; and (iii) cognate or noncognate cellular interactions that enhance the response of other cell types, particularly CD4+ T cells. Here, we were interested primarily in identifying the role of the virus-specific Ab response. This was done by adoptive transfer of spleen cells into B-cell-deficient and CD8+ T-cell-depleted hosts, termed μMT(−8), using B cells that differed in ability to generate virus-specific Abs or participate in the TD Ab response. The recipient mice were then tested for ability to resolve a primary infection with influenza virus. The results provide evidence for a major therapeutic role of the TD and lesser role of the TI Ab response. Furthermore, they reveal a significant therapeutic synergism between Ab- and CD4+ T-cell-mediated activities.