Trends in Immunology
IFNγR2 trafficking tunes IFNγ–STAT1 signaling in T lymphocytes
Section snippets
IFNγ and the IFNγR complex
According to the current IFNγ signaling model, a dimeric IFNγ molecule binds to two IFNγR1 chains, which prompts the association of two IFNγR2 subunits with two IFNγ-bound IFNγR1 chains. IFNγR1 and IFNγR2 are constitutively associated with the inactive forms of the tyrosine kinases Jak1 and Jak2, respectively 1, 2. After receptor complex assembly, Jak1 and Jak2 transactivate each other and phosphorylate Tyr440 of IFNγR1 to generate a docking site for STAT1. After its recruitment, STAT1 is
IFNγR2 expression and negative regulation of the IFNγ–STAT1 pathway
IFNγR1 expression is ubiquitous [25], whereas that of IFNγR2 is fine-tuned by many factors that determine the outcome of IFNγ–STAT1-dependent responses. In T cells, the IFNγ–STAT1 pathway is predominantly activated in naïve and Th2 cells because they express IFNγR2 4, 5 and hence are sensitive to the antiproliferative effect of IFNγ [26]. Loss of IFNγR2 is characteristic of the CD4+ cell response to IFNγ exposure, rather than being the result of a specific gene expression event during Th1
IFNγR2 upregulation and IFNγ–STAT1-dependent apoptosis
Internalization of IFNγR2 appears to be T cell specific. Other hematopoietic cells, such as B cells and macrophages, express higher amounts of surface IFNγR2 and undergo apoptosis when the IFNγ–STAT1 pathway is activated [22]. The high expression of IFNγR2 on macrophages is likely to favor the IFNγ-mediated apoptosis of mycobacteria-infected macrophages 37, 38. IFNγ does not affect IFNγR2 expression on macrophages [39], although its internalization is induced by the stimulation of Toll-like
Ligand-independent internalization of IFNγR2
The existence of ligand-independent internalization of IFNγR2 has been deduced from several observations. T cells unable to produce IFNγ display internalized IFNγR2 22, 23. Absence of IFNγR2 surface accumulation has also been observed on T cells from healthy donors and patients with complete IFNγR1 deficiency [33]. The co-localization of IFNγR2 with transferrin receptor (TfR) and cytotoxic T lymphocyte-associated antigen 4, two cell-surface receptors whose trafficking involves clathrin-coated
Factors inducing IFNγR2 internalization
Identification of factors responsible for T cell IFNγR2 internalization starts from the observation that T cell lines unable to produce IFNγ accumulate IFNγR2 on their surface when cultured in the absence of serum [22]. Factors or hormones contained in serum are responsible for IFNγR2 internalization (Figure 1).
Ligand-independent internalization of IFNγR2 in the regulation of immune responses
Internalization of IFNγR2 protects T cells from IFNγ-induced apoptosis. Its surface re-expression might occur during the lifetime of a T cell and correlates with the ability of IFNγ to induce STAT1-dependent apoptosis. IFNγ-induced downregulation of IFNγR2 has a crucial role during Th1 development, whereas ligand-independent IFNγR2 internalization, mostly induced by IGF-1 and iron, affects activated T cells, irrespective of their ability to produce IFNγ. However, in induction of all of the
Acknowledgements
We thank F.H. Bach and J. Iliffe for critical reading of the article and the present and former members of the Laboratory of Tumor Immunology for helpful discussions. This work was supported, in part, by grants from the Compagnia di San Paolo (special project Oncology), Associazione italiana Ricerca sul Cancro (AIRC), Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN) and Fondo per l'Innovazione e la Ricerca di Base (FIRB) and
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