The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation

Zheng Wu, Hai Hui Xue, Jérôme Bernard, Rong Zeng, Dmitry Issakov, Julie Bollenbacher-Reilley, Igor M. Belyakov, SangKon Oh, Jay A. Berzofsky, Warren J. Leonard

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

IL-15 is critical for natural killer (NK) - cell development and function and for memory CD8+ T-cell homeostasis. The IL-15 receptor consists of IL-15Rα, IL-2Rβ, and the common cytokine receptor γ chain (γ c). IL-15Rα is known to "trans-present" IL-15 to an IL-2Rβ/γ c heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Rα cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Rα and intracellular do-main of IL-2Rα (IL-15Rα ext/IL-2Rα int) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8 + T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15 - induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Rα expression, indicating a signaling role for the IL-15Rα cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Ra and IL-15Rα cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Rα ext/ IL- 2Rα int receptor still supports trans-presentation. These experiments collectively indicate that IL-15Rα can act in cis in addition to acting in transto present IL-15 to responding cells.

Original languageEnglish (US)
Pages (from-to)4411-4419
Number of pages9
JournalBlood
Volume112
Issue number12
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

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Interleukin-15 Receptors
Interleukin-15
T-cells
Adoptive Transfer
T-Lymphocytes
Cytokine Receptors
Experiments
Natural Killer Cells
Cells
Data storage equipment
Homeostasis
Defects
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Wu, Z., Xue, H. H., Bernard, J., Zeng, R., Issakov, D., Bollenbacher-Reilley, J., ... Leonard, W. J. (2008). The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation. Blood, 112(12), 4411-4419. https://doi.org/10.1182/blood-2007-03-080697

The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation. / Wu, Zheng; Xue, Hai Hui; Bernard, Jérôme; Zeng, Rong; Issakov, Dmitry; Bollenbacher-Reilley, Julie; Belyakov, Igor M.; Oh, SangKon; Berzofsky, Jay A.; Leonard, Warren J.

In: Blood, Vol. 112, No. 12, 01.12.2008, p. 4411-4419.

Research output: Contribution to journalArticle

Wu, Z, Xue, HH, Bernard, J, Zeng, R, Issakov, D, Bollenbacher-Reilley, J, Belyakov, IM, Oh, S, Berzofsky, JA & Leonard, WJ 2008, 'The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation', Blood, vol. 112, no. 12, pp. 4411-4419. https://doi.org/10.1182/blood-2007-03-080697
Wu, Zheng ; Xue, Hai Hui ; Bernard, Jérôme ; Zeng, Rong ; Issakov, Dmitry ; Bollenbacher-Reilley, Julie ; Belyakov, Igor M. ; Oh, SangKon ; Berzofsky, Jay A. ; Leonard, Warren J. / The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation. In: Blood. 2008 ; Vol. 112, No. 12. pp. 4411-4419.
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AU - Issakov, Dmitry

AU - Bollenbacher-Reilley, Julie

AU - Belyakov, Igor M.

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AB - IL-15 is critical for natural killer (NK) - cell development and function and for memory CD8+ T-cell homeostasis. The IL-15 receptor consists of IL-15Rα, IL-2Rβ, and the common cytokine receptor γ chain (γ c). IL-15Rα is known to "trans-present" IL-15 to an IL-2Rβ/γ c heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Rα cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Rα and intracellular do-main of IL-2Rα (IL-15Rα ext/IL-2Rα int) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8 + T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15 - induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Rα expression, indicating a signaling role for the IL-15Rα cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Ra and IL-15Rα cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Rα ext/ IL- 2Rα int receptor still supports trans-presentation. These experiments collectively indicate that IL-15Rα can act in cis in addition to acting in transto present IL-15 to responding cells.

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