Trends in Immunology
OpinionIFN-γ production by antigen-presenting cells: mechanisms emerge
Section snippets
The classical model
The interaction between APCs and T cells is important in determining the effectiveness of the immune response to pathogens. In the classical model, a crucial step in the control of intracellular pathogens is the early production of IFN-γ by NK cells and subsequently, CD4+ T cells. IFN-γ enhances the antigen-presenting capabilities of dendritic cells (DCs) and macrophages, and promotes the killing of intracellular pathogens in macrophages. APCs regulate this process by producing interleukin-12
IFN-γ production by APCs: controversial observations that are gaining acceptance
It has long been known that IFN-γ is produced not only by CD4+ and CD8+ T cells but also, by γδ T cells, NK cells and NKT cells, allowing rapid responses in the absence of specific T-cell recognition of pathogens 9, 10. Recently, it was reported that B cells also produce IFN-γ (11, 12, 13). However, the suggestion that myeloid cells produce IFN-γ has proved controversial. As early as 1985, alveolar macrophages from humans with pulmonary sarcoidosis were reported to produce IFN-γ (Ref. 14).
Regulation of IFN-γ production in APCs
A variety of transcription factors regulate the production of IFN-γ by activated T cells [e.g. signal transducer and activator of transcription 4 (STAT4) and T-bet], although their precise mechanisms of action are still unknown. The production of IFN-γ by APCs requires cellular activation also and, as for T cells, cytokines appear to be key regulators. In human alveolar macrophages, the expression of IFN-γ was reported in autoimmune disease states, such as sarcoidosis, or following infection
IL-12R subunit expression in APCs
The responses of APCs to IL-12 and the subsequent evidence of IL-12-dependent signal transduction imply that a functional IL-12R is present on APCs. In T cells, the expression of IL-12R subunits is regulated tightly by cell activation and Th2 cytokines 34. However, regulation of the expression of IL-12R subunits in APCs has not been studied in detail. In murine resting peritoneal macrophages, the expression of IL-12R β1 and β2 mRNA increases with time in culture. Stimulation with IL-12 further
Requirement for STAT4 for IFN-γ production by APCs
Although the functional relevance of STAT4 signaling in lymphoid cells is clear, it is important also to establish the importance of STAT4 in APC functions. Studies using STAT4−/− mice have confirmed the essential role of STAT4 in the IL-12-dependent production of IFN-γ by APCs. Bone-marrow-derived macrophages, peritoneal macrophages and splenic DCs all require STAT4 for the production of IFN-γ in response to IL-12 (25, 28). STAT4 is also required for IFN-γ-dependent processes, such as the
Conclusions and future directions
Previous models have focused on the role of lymphoid cells in the production of IFN-γ. Although the importance of lymphoid IFN-γ production is indisputable, it is relevant to underscore the potential role of APC-derived IFN-γ at certain key points during immune responses. It is proposed that, along with NK-cell-derived IFN-γ, APC-derived IFN-γ might play an important role in the initial stages of infection, prior to specific recognition by T cells. Even small amounts of IFN-γ produced by
Acknowledgements
We thank M. Gadina and T. Ohteki for discussion. The work of the authors was supported in part by a grant from the Japanese Society for the Promotion of Science (JSPS-RFTF 97L00701). D.F. and T.F. contributed equally to the preparation of this manuscript.
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