Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells

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Abstract

The molecular basis for the different roles of IL-2 and IL-15 in lymphocyte function has been poorly defined. Searching for differences that underlie the distinct T cell responses to the two cytokines, we observed a marked susceptibility of the IL-15-induced but not of the IL-2-induced proliferation to rapamycin despite a decrease of p70S6 kinase (p70 S6K) activation by the drug in response to both cytokines. Activated splenic T lymphocytes deficient in the FK506-binding protein (FKBP) 12, a target of rapamycin activity, had reduced proliferation in response to IL-15 but not to IL-2. This decreased proliferation was accompanied by reduced activation of p70S6K and of the extracellular signal-regulated kinases (ERK) after IL-15 treatment. In contrast to FKBP12-/- cells, splenic FKBP12.6-/- T cells exhibited a decreased proliferative response to IL-2 in the presence of rapamycin without affecting p70 S6K or ERK activation. Thus, IL-15 induces T cell proliferation mainly via FKBP12-mediated p70S6K activation. In contrast, IL-2 signaling involves multiple pathways that include at least one additional pathway that depends on FKBP12.6.

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Dubois, S., Shou, W., Haneline, L. S., Fleischer, S., Waldmann, T. A., & Müller, J. R. (2003). Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells. Proceedings of the National Academy of Sciences of the United States of America, 100(SUPPL. 2), 14169–14174. https://doi.org/10.1073/pnas.2335979100

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