Jill O. de Jong 1990-1999
Woman & Children's Hospital, Boston, MA
University of Chicago 1990
Human Oncology PhD 1997
Paul Sondel
Functional responses and receptor usage of human lymphocytes in response to interlukin-2 and interlukin-15
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Interleukin-2 (IL-2) and Interleukin-15 (IL-15) both activate T cells, natural killer (NK) cells and B cells. All three of these cell types express the IL-2 receptor beta (IL-2beta) and common gamma (gamma/c) subunits which are both involved in the response to IL-2 and IL-15 and required for signal transduction. Despite this joint usage, distinct cellular responses are induced by IL-2 and IL-15, suggesting that differences in receptor usage might exist. I have pursued the hypothesis that IL-2 and IL-15 activate quantitatively different responses by human lymphocytes, and that these differences result from different receptor-ligand interactions.
Cells bearing either high affinity (alpha beta gamma/c) or intermediate affinity (beta gamma chi) IL-2R complexes required a greater dose of IL-15 than IL-2 to stimulate a comparable level of proliferation. Blocking these proliferative responses with anti-IL-2R alpha or anti-IL-2 R beta antibodies suggested that IL-15 may not interact as strongly with the IL-2R beta subunit as does IL-2, independent of the influence of the IL-2R alpha molecule. Covalent cross-linking experiments indicated that IL-15 physically interacts with the IL-2R beta and gamma/c chains, but not the IL-2R alpha chain. High affinity IL-15 binding was documented by Scatchard analysis on YT cells bearing intermediate affinity IL-2 receptors. Despite this, co-immunoprecipitation of the IL-2R beta and gamma/c subunits from YT cells was readily documented in the presence of IL-2, but could not be reproduced using IL-15. Therefore, the trimolecular IL-2/beta/gamma/c complex was more stable than the IL-15/beta/gamma/c complex, and high affinity IL-15 binding may occur independently of the beta/gamma/c complex.
To ask whether these receptor differences applied to a clinically relevant cell population, peripheral blood mononuclear cells (PBMC) from cancer patients receiving in vivo IL-2 therapy were tested. Again, a greater dose of IL-15 than IL-2 was required to stimulate a comparable proliferative response by these PBMC in vitro. However, similar doses of IL-2 or IL-15 induced the same level of cytotoxicity against tumor targets in vitro. These dose-response differences between IL-2 and IL-15 are consistent with postulated decreases in IL-15R alpha expression, which confers high affinity IL-15 binding. However, further studies are needed to confirm the potential usefulness of IL-15 as an immunotherapeutic agent for the treatment of cancer. |
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| Thesis Publications |
- Monson NL, Fenske TJ, Wei S, Okragly AJ, de Jong JL, Haak-Frendscho M, O'Shea J, Djeu, Sondel PM . A p74 common gamma receptor chain isoform facilitates IL-2 and IL-15 responses by the myelomonocytic cell line Tf-1beta2. J Leukoc Biol 69:419-425, 2001.
- de Jong JL, Farner NL, Sondel PM. Distinctions in lymphocyte responses to IL-2 and IL-15 reflect differential ligand binding interactions with the IL-2Rbeta chain and suggest differential roles for the IL-2Ralpha and IL-15Ralpha subunits. Cytokine 10:920-30, 1998.
- de Jong JL, Farner NL, Javorsky BR, Lindstrom MJ, Hank JA, Sondel PM. Differential quantitative effects of interleukin (IL)-2 and IL-15 on cytotoxic activity and proliferation by lymphocytes from patients receiving in vivo IL-2 therapy. Clin Cancer Res. 4:1287-96, 1998.
- Farner NL, Gan J, de Jong JL, Leary TP, Fenske TS, Buckley P, Dunlap S, Sondel PM. Alteration of the CD34+ Tf-1beta cell line profile in response to long-term exposure to IL-15. Cytokine. 9:316-27, 1997.
- de Jong JL, Farner NL, Widmer MB, Giri JG, Sondel PM. Interaction of IL-15 with the shared IL-2 receptor beta and gamma c subunits. The IL-15/beta/gamma c receptor-ligand complex is less stable than the IL-2/beta/gamma c receptor-ligand complex. J Immunol. 156:1339-48, 1996.
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