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Subtypes in Human T Cells and Dendritic Cells 1,2
Cancer Research UK London Research Institute, Lincoln’s Inn Fields Laboratories, London, United Kingdom
Type I IFNs (IFN-
) constitute a family of cytokines that have important antiviral and immunoregulatory properties and have been successfully used in the treatment of a wide variety of diseases. There are 12 functional human IFN- subtypes and one IFN- subtype that signal through the common cell surface IFN-R. To date, virtually no information is available on the specificity of IFN- responses in immune cells. In this study, Janus kinase/STAT signaling and transcriptional responses to selected IFN- subtypes in human T cells and dendritic cells were analyzed. Evidence for IFN- subtype and cell type specificity was found. Also, differences between kinetics of expression of IFN-stimulated genes (ISGs) and in the requirements of individual ISGs for additional signaling pathways were observed. In particular, IFN-
-inducible protein-10 (IP-10), a key chemokine in Th1-type inflammatory diseases, was differentially regulated. In dendritic cells, it was highly induced by IFN-2 and IFN-21 but much less efficiently by IFN-1. It was only marginally induced by these subtypes in T cells. In marked contrast to other ISGs analyzed, optimum induction of IP-10 was dependent on activation of p38 kinase(s). The observed variations (subtype-, cell type-, and ISG-related differentials) provide further insight into the complexity and plasticity of the IFN- response. Furthermore, the novel observation that IFN-1 poorly induces IP-10 is potentially of clinical importance, because this subtype may be more beneficial in cases where Th1-mediated side effects (e.g., exacerbation of autoimmune diseases) are not desirable.
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