Article: article from journal or magazin.
Strong TCR signaling, TLR ligands, and cytokine redundancies ensure robust development of type 1 effector T cells.
Journal of Immunology
T cell effector function is a central mechanism of adaptive immunity, and accordingly, protection of the host against pathogens. One of the primary effector molecules produced by T cells in response to such pathogens is the cytokine, IFN-gamma. Although the signaling pathways associated with the production of IFN-gamma are well established, disparate in vivo and in vitro results indicate that distinct pathways may become more prominent dependent upon the nature of the infection, inflammatory milieu and tissue localization. We have examined the roles and requirements of the major IFN-gamma-inducing pathways in vivo and in vitro, specifically: strength of TCR signal; paracrine release of IL-12, IL-23, and IL-18; and autocrine production of IFN-gamma. Our data show a dynamic interaction between these activation pathways, which allows the host a degree of flexibility and redundancy in the induction of IFN-gamma. Upon strong signaling through the TCR, IL-12, IL-18, and IL-23 play negligible roles in the induction of IFN-gamma, whereas autocrine IFN-gamma is an important component in sustaining its own secretion. However, the absence of any one of these factors during a weaker TCR signal, results in strikingly impaired T cell IFN-gamma production. Of note, TLR-activated dendritic cells (DCs) were capable of overcoming the absence of a strong TCR signal, IL-12, IL-23, or IL-18 revealing an important additional mechanism for ensuring a robust IFN-gamma response. Our findings clarify the hierarchical requirements of the major IFN-gamma inducing pathways and highlight the important role TLR ligand-activated DCs have to preserve them.
Animals, Antigens, Viral/metabolism, Antigens, Viral/physiology, CD8-Positive T-Lymphocytes/cytology, CD8-Positive T-Lymphocytes/immunology, Cell Differentiation/genetics, Cell Differentiation/immunology, Cell Proliferation, Cells, Cultured, Coculture Techniques, Cytokines/biosynthesis, Cytokines/physiology, Dose-Response Relationship, Immunologic, Glycoproteins/metabolism, Glycoproteins/physiology, Interferon-gamma/biosynthesis, Interleukin-12/deficiency, Interleukin-12/genetics, Interleukin-18/deficiency, Interleukin-18/genetics, Ligands, Lymphocytic choriomeningitis virus/immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Peptide Fragments/metabolism, Peptide Fragments/physiology, Receptors, Antigen, T-Cell/deficiency, Receptors, Antigen, T-Cell/genetics, Signal Transduction/genetics, Signal Transduction/immunology, Th1 Cells/cytology, Th1 Cells/immunology, Toll-Like Receptors/metabolism, Toll-Like Receptors/physiology, Viral Proteins/metabolism, Viral Proteins/physiology
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