It is generally believed that the production of influenza-specific IgG in response to viral infection is dependent on CD4 T cells. However, we previously observed that CD40-deficient mice generate influenza-specific IgG during a primary infection, suggesting that influenza infection may elicit IgG responses independently of CD4 T cell help. In the present study, we tested this hypothesis and show that mice lacking CD40 or CD4 T cells produce detectable titers of influenza-specific IgG and recover from influenza infection in a manner similar to that of normal mice. In contrast, mice completely lacking B cells succumb to influenza infection, despite the presence of large numbers of functional influenza-specific CD8 effector cells in the lungs. Consistent with the characteristics of a T-independent Ab response, long-lived influenza-specific plasma cells are not found in the bone marrow of CD40−/− and class II−/− mice, and influenza-specific IgG titers wane within 60 days postinfection. However, despite the short-lived IgG response, CD40−/− and class II−/− mice are completely protected from challenge infection with the same virus administered within 30 days. This protection is mediated primarily by B cells and Ab, as influenza-immune CD40−/− and class II−/− mice were still resistant to challenge infection when T cells were depleted. These data demonstrate that T cell-independent influenza-specific Ab promotes the resolution of primary influenza infection and helps to prevent reinfection.
CD40 ligand (CD154) expression on activated T cells can be separated into an early TCR-dependent phase, which occurs between 0 and 24 h after activation, and a later extended phase, which occurs after 24 h and is reciprocally regulated by the cytokines IL-4 and IL-12. IL-4 represses, whereas IL-12 sustains CD154 expression. Consistent with this, Th1, but not Th2, cells express CD154 for extended periods. Differences in the duration of CD154 expression have important biological consequences because sustained, but not transient, expression of CD154 on activated T cells can prevent B cell terminal differentiation. Thus, the differential ability of Th cells to sustain CD154 expression is an important part of their helper function and should influence the activities of other CD40-expressing cell types.
Lymphotoxin-α−/− (LTα−/−) mice are thought to be unable to generate effective T and B cell responses. This is attributed to the lack of lymph nodes and the disrupted splenic architecture of these mice. However, despite these defects we found that LTα−/− mice could survive infection with a virulent influenza A virus. LTα−/− mice and normal wild-type mice infected with influenza A generated similar numbers of influenza-specific CD8 T cells that were able to produce IFN-γ and kill target cells presenting influenza peptides. Furthermore influenza-infected LTα−/− mice produced high titers of influenza-specific IgM, IgG, and IgA. However, both CD8 and B cell immune responses were delayed in LTα−/− mice by 2–3 days. The delayed cellular and humoral immune response was sufficient to mediate viral clearance in LTα−/− mice that were infected with relatively low doses of influenza virus. However, when LTα−/− mice were infected with larger doses of influenza, they succumbed to infection before the immune response was initiated. These results demonstrate that neither LTα nor constitutively organized lymphoid tissues, such as lymph nodes and spleen, are absolutely required for the generation of effective immunity against the respiratory virus influenza A. However, the presence of LTα and/or lymph nodes does accelerate the initiation of immune responses, which leads to protection from larger doses of virus.
Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells (DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4+ T cells than splenic B2 cells. This was demonstrated by direct HBcAg-biotin-binding studies and by HBcAg-specific T cell activation in vitro in cultures of naive HBcAg-specific T cells and resting B cell subpopulations. The inability of DC to function as APCs for exogenous HBcAg relates to lack of uptake of HBcAg, not to processing or presentation, because HBcAg/anti-HBc immune complexes can be efficiently presented by DC. Furthermore, HBcAg-specific CD4+ and CD8+ T cell priming with DNA encoding HBcAg does not require B cell APCs. TLR activation, another innate immune response, was also examined. Full-length (HBcAg183), truncated (HBcAg149), and the nonparticulate HBeAg were screened for TLR stimulation via NF-κB activation in HEK293 cells expressing human TLRs. None of the HBc/HBeAgs activated human TLRs. Therefore, the HBc/HBeAg proteins are not ligands for human TLRs. However, the ssRNA contained within HBcAg183 does function as a TLR-7 ligand, as demonstrated at the T and B cell levels in TLR-7 knockout mice. Bacterial, yeast, and mammalian ssRNA encapsidated within HBcAg183 all function as TLR-7 ligands. These studies indicate that innate immune mechanisms bridge to and enhance the adaptive immune response to HBcAg and have important implications for the use of hepadnavirus core proteins as vaccine carrier platforms.
Two models have been proposed to explain the requirement for CD40 signaling in CD8 T cell responses. The first model suggests that CD4 T cells activate antigen-presenting cells (APCs) through CD40 signaling (APC licensing). In turn, licensed APCs are able to prime naive CD8 T cells. The second model suggests that CD154-expressing CD4 T cells activate CD40-bearing CD8 T cells directly. Although the requirement for CD40 in APC licensing can be bypassed by inflammatory responses to pathogens that activate APCs directly, the second model predicts that CD8 responses to all antigens will be dependent on CD40 signaling. Here we determined which model applies to CD8 responses to influenza. We demonstrate that optimal CD8 T cell responses to influenza are dependent on CD40 signaling, however both primary and secondary responses to influenza require CD40 expression on non–T cells. Furthermore, CD40−/− CD8 T cells proliferate and differentiate to the same extent as CD40+/+ CD8 T cells in response to influenza, as long as they have equal access to CD40+/+ APCs. Thus, CD4 T cells do not activate influenza-specific CD8 cells directly through CD40 signaling. Instead, these data support the classical model, in which CD4 T cells provide help to CD8 T cells indirectly by activating APCs through CD40.
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