Quantitative analysis of IL-2 and IL-15 signal transduction in T lymphocytes
Quantitative analysis of the Interleukin-2/15 receptor signaling in T lymphocytes
Massachusetts Institute of Technology. Department of Biological Engineering.
Forest M. White and Douglas A. Lauffenburger.
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IL-2 and IL-15 are common y-chain family cytokines critically involved in regulation of T cell differentiation and homeostasis. Both cytokines signal through a heterotrimeric surface receptor complex (IL-2/15R) composed of an [alpha], a [beta], and the common gamma ([gamma]c) chain. Signaling occurs through the shared [beta] and [gamma]c chains, and the a-chains function as high affinity ligand capture agents. Despite sharing signaling chains and pathways, IL-2 and IL-15 have nonredundant roles in T cell biology. In vitro, although IL-2 and IL-15 function as equivalent mitogens, they greatly differ in their activities as growth factors. T cells cultured with IL-2 are larger in size, show increased protein synthesis, and increased amino-acid uptake compared to T cells cultures in IL-15. Additionally, transient exposure of T cell to IL-15, but not IL-2, results in prolonged survival and proliferation after cytokine withdrawal. In vivo, IL-2 is critical for the initial clonal expansion and contraction of activated T cells, whereas IL-15 is critical for the differentiation, and maintenance of memory T cells. The mechanisms through which IL-2 and IL- 15 trigger distinct phenotypes while initiating identical signaling pathways remain elusive. Using mass spectrometry based proteomics, we found that IL-2 and IL-15 trigger a quantitatively and qualitatively identical phosphotyrosine signaling response in T cells. The distinct effects of IL-2 and IL-15 on T cells could not be explained through activation of qualitatively distinct signaling pathways. Instead, our results show that IL-2 and IL-15 mediate distinct T cell phenotypes through differential regulation of IL-2/15R signal strength and duration. The increased survival and proliferation of T cells in response to transient IL-15 exposure is mediated through its ability to trigger prolonged signaling through the IL-2/15R after cytokine withdrawal. Furthermore, we find that T cell proliferation in response to IL-2 and IL-15 stimulation requires a constant signal input from the IL-2/15R. Additionally, T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Proliferation is controlled by signal strength in a digital manner, whereas cell size and metabolism are controlled in an analog fashion. The differences in cytokinereceptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokinereceptor intracellular trafficking kinetics can result in the differential regulation of IL-2/15R signal strength and duration by IL-2 and IL-15. These results suggest that IL-2 and IL-15 can trigger distinct phenotypes by differentially regulating the strength and duration of IL-2/15R signal transduction, without having to activate distinct biochemical signaling pathways. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2013.Title as it appears in MIT Degree awarded booklet, February 2013: Quantitative analysis of the Interleukin-2/15 receptor signaling in T lymphocytes. Cataloged from PDF version of thesis.Includes bibliographical references (p. 168-183).
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering.; Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology