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In this report, we sought to determine the role of selected type I interferons [interferon-α (IFN-α) and interferon-τ (IFN-τ)], IFN-γ and transforming growth factor-β (TGF-β) in the regulation of bovine antibody responses. B cells were stimulated via CD40 in the presence or absence of B-cell receptor (BCR) cross-linking. IFN-α enhanced IgM, IgG2 and IgA responses but did not enhance IgG1 responses. BCR signalling alone was more effective at inducing IgG2 responses with IFN-α than dual cross-linking with CD40. Recombinant ovine IFN-τ was less effective at inducing IgG2 responses when compared with IFN-α, though IgA responses were similar in magnitude following BCR cross-linking. At higher concentrations, IFN-τ enhanced IgA responses greater than twofold over the levels observed with IFN-α. Previous studies have shown that addition of IFN-γ to BCR or pokeweed mitogen-activated bovine B cells stimulates IgG2 production. However, following CD40 stimulation alone, IFN-γ was relatively ineffective at stimulating high-rate synthesis of any non-IgM isotype. Dual cross-linking via CD40 and the BCR resulted in decreased synthesis of IgM with a concomitant increase in IgA and similar levels of IgG2 production to those obtained via the BCR alone. We also assessed the effects of endogenous and exogenous TGF-β on immunoglobulin synthesis by bovine B cells. Exogenous TGF-β stimulates both IgG2 and IgA production following CD40 and BCR cross-linking in the presence of IL-2. Blocking endogenous TGF-β did not inhibit the up-regulation of IgG2 or IgA by interferons.