Editors' ChoiceImmunology

Alternatively Spliced into an Inhibitor

Science Signaling  01 Jul 2014:
Vol. 7, Issue 332, pp. ec181
DOI: 10.1126/scisignal.2005643

Cytokines of the common γ-chain family signal through cell-surface receptors that consist of cytokine-specific subunits and a shared γ-chain (γc) subunit. The γc subunit is a transmembrane protein that contains an extracellular region for ligand-binding and a cytoplasmic tail that is required for intracellular signaling. Cytokines of the γc family, which include interleukin-2 (IL-2) and IL-7, are critical for the development and survival of various T cell subsets. Hong et al. found that the culture medium of activated mouse T cells contained a soluble form of γc (sγc), which contained the extracellular, but not the transmembrane or cytoplasmic, regions of γc. The sγc protein was generated not by the shedding of cell-surface γc but through an alternatively spliced γc mRNA that was increased in abundance in activated T cells. Mice injected with a T cell–activating antibody had increased serum concentrations of sγc. In a mouse model of multiple sclerosis, overexpression of sγc led to increased inflammation and worse disease, which was associated with increased numbers of pro-inflammatory T helper 1 (TH1) and TH17 cells. Conversely, disease was less severe in transgenic mice that expressed only the membrane-bound form of γc. Western blotting analysis showed that IL-2 signaling was decreased in cultured T cells exposed to sγc compared with that in control T cells exposed to IL-2. Binding assays and flow cytometric analysis showed that sγc bound to the IL-2 receptor β-subunit and that the affinity of sγc for IL-2Rβ was enhanced in the presence of IL-2. In vitro, sγc enhanced the generation of TH17 cells, which depended on inhibition of IL-2 signaling. Finally, in vitro and in vivo experiments showed that sγc also blocked signaling by IL-7. Thus, these data suggest that sγc inhibits specific cytokine responses, which can promote autoimmunity (see commentary by Jameson and Renkema).

C. Hong, M. A. Luckey, D. L. Ligons, A. T. Waickman, J.-Y. Park, G. Y. Kim, H. R. Keller, R. Etzensperger, X. Tai, V. Lazarevic, L. Feigenbaum, M. Catalfamo, S. T. R. Walsh, J.-H. Park, Activated T cells secrete an alternatively spliced form of common γ-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity 40, 910–923 (2014). [PubMed]

S. C. Jameson, K. R. Renkema, An uncommon tail about the common γ-chain. Immunity 40, 859–860 (2014). [PubMed]