ABSTRACT
Type I IFN (IFN-alphabeta), which is produced rapidly in response to infection, plays a key role in innate immunity and also acts as a stimulus for the adaptive immune response. We have investigated how IFN-alphabeta induces cross-priming, comparing CD8+ T cell responses generated against soluble protein Ags in the presence or absence of IFN-alphabeta. Injection of IFN-alpha was found to prolong the proliferation and expansion of Ag-specific CD8+ T cells, which was associated with marked up-regulation of IL-2 and IL-15 receptors on Ag-specific cells and expression of IL-15 in the draining lymph node. Surprisingly, neither IL-2 nor IL-15 was required for IFN-alpha-induced cross-priming. Conversely, expression of the IFN-alphabetaR by T cells was shown to be necessary for effective stimulation of the response by IFN-alpha. The finding that T cells represent direct targets of IFN-alphabeta-mediated stimulation reveals an additional mechanism by which the innate response to infection promotes adaptive immunity.
Subject(s)
CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Interferon-alpha/pharmacology , Adoptive Transfer , Animals , Antigen Presentation , Base Sequence , CD8-Positive T-Lymphocytes/cytology , Cell Proliferation , Cross Reactions , DNA, Complementary/genetics , Immunity, Innate , In Vitro Techniques , Interleukin-15/genetics , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/immunology , Radiation Chimera/immunology , Receptor, Interferon alpha-beta , Receptors, Interferon/deficiency , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Receptors, Interleukin-15 , Receptors, Interleukin-2/metabolismABSTRACT
Type I IFN (IFN-alphabeta) is induced rapidly by infection and plays a key role in innate antiviral defense. IFN-alphabeta also exerts stimulatory effects on the adaptive immune system and has been shown to enhance Ab and T cell responses. We have investigated the importance of B and T cells as direct targets of IFN-alphabeta during IFN-alpha-mediated augmentation of the Ab response against a soluble protein Ag. Strikingly, the ability of IFN-alpha to stimulate the Ab response and induce isotype switching was markedly reduced in mice in which B cells were selectively deficient for the IFN-alphabetaR. Moreover, IFN-alpha-mediated enhancement of the Ab response was also greatly impaired in mice in which T cells were selectively IFN-alphabetaR-deficient. These results indicate that IFN-alphabetaR signaling in both B and T cells plays an important role in the stimulation of Ab responses by IFN-alphabeta.
Subject(s)
Antibody Formation/immunology , B-Lymphocytes/immunology , Interferon Type I/immunology , T-Lymphocytes/immunology , Animals , Antibody Formation/drug effects , B-Lymphocytes/drug effects , Gene Expression Regulation , Interferon Type I/pharmacology , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptor, Interferon alpha-beta , Receptors, Interferon/deficiency , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , T-Lymphocytes/drug effectsABSTRACT
CD8+ T cell responses can be generated against antigens that are not expressed directly within antigen-presenting cells (APCs), through a process known as cross-priming. To initiate cross-priming, APCs must both capture extracellular antigen and receive specific activation signals. We have investigated the nature of APC activation signals associated with virus infection that stimulate cross-priming. We show that infection with lymphocytic choriomeningitis virus induces cross-priming by a mechanism dependent on type I interferon (IFN-alpha/beta). Activation of cross-priming by IFN-alpha/beta was independent of CD4+ T cell help or interaction of CD40 and CD40 ligand, and involved direct stimulation of dendritic cells. These data identify expression of IFN-alpha/beta as a mechanism for the induction of cross-priming during virus infections.
