The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15Ralpha function but is not required for trans-presentation.
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-15Ralpha, IL-2Rbeta, and the common cytokine receptor gamma chain (gamma(c)). IL-15Ralpha is known to "trans-present" IL-15 to an IL-2Rbeta/gamma(c) heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Ralpha cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Ralpha and intracellular domain of IL-2Ralpha (IL-15Ralpha(ext)/IL-2Ralpha(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-15Ralpha expression, indicating a signaling role for the IL-15Ralpha cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Ralpha and IL-15Ralpha cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Ralpha(ext)/IL-2Ralpha(int) receptor still supports trans-presentation. These experiments collectively indicate that IL-15Ralpha can act in cis in addition to acting in trans to present IL-15 to responding cells.
Wu
Zheng
Z
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
Xue
Hai-Hui
HH
Bernard
Jérôme
J
Zeng
Rong
R
Issakov
Dmitry
D
Bollenbacher-Reilley
Julie
J
Belyakov
Igor M
IM
Oh
Sangkon
S
Berzofsky
Jay A
JA
Leonard
Warren J
WJ
D019264:Adoptive Transfer / Q000662:veterinary; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D014162:Transfection
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007371:Interferon-gamma
Cell. 1993 Apr 9;73(1):147-57
8462096
Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
16911870
J Immunol. 2002 May 15;168(10):4827-31
11994430
Immunity. 2002 Nov;17(5):537-47
12433361
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2077-82
8700888
Immunol Rev. 2003 Jun;193:70-81
12752672
Science. 1985 Nov 8;230(4726):633-9
2996141
Int J Hematol. 2001 Apr;73(3):271-7
11345192
J Exp Med. 2004 Oct 4;200(7):825-34
15452177
J Immunol. 1985 Jun;134(6):4212-7
3921620
Immunol Rev. 2004 Dec;202:67-83
15546386
J Exp Med. 2002 Jun 17;195(12):1541-8
12070282
Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15154-9
15477598
J Exp Med. 2001 Oct 15;194(8):1187-94
11602647
J Immunol. 2003 May 15;170(10):5018-26
12734346
J Immunol. 2004 Aug 1;173(3):1681-8
15265897
J Exp Med. 1994 Oct 1;180(4):1395-403
7523571
Annu Rev Immunol. 2002;20:551-79
11861612
Immunity. 1998 May;8(5):591-9
9620680
FASEB J. 1999 Sep;13(12):1575-85
10463949
J Exp Med. 2005 Jan 3;201(1):95-104
15623576
Anal Biochem. 1982 Nov 15;127(1):143-9
6762105
Cytokine Growth Factor Rev. 1997 Dec;8(4):313-32
9620644
Science. 2002 Nov 22;298(5598):1630-4
12446913
EMBO J. 1995 Aug 1;14(15):3654-63
7641685
J Cell Biol. 1995 Apr;129(1):55-64
7698995
Immunity. 1995 Oct;3(4):521-30
7584142
Immunity. 1998 Nov;9(5):669-76
9846488
Blood. 2001 Jan 1;97(1):14-32
11133738
Immunity. 1996 Apr;4(4):329-36
8612127
Science. 2000 Apr 28;288(5466):675-8
10784451
J Immunol. 2001 Dec 1;167(11):6292-302
11714793
J Exp Med. 1982 Jun 1;155(6):1823-41
6176669
J Biol Chem. 2004 Sep 24;279(39):40368-75
15215246
Cytokine Growth Factor Rev. 2002 Dec;13(6):429-39
12401478
Int J Biochem Cell Biol. 2005 Aug;37(8):1567-71
15896666
J Biol Chem. 1995 Dec 15;270(50):29862-9
8530383
Adv Immunol. 2005;86:209-39
15705423
J Leukoc Biol. 1995 May;57(5):763-6
7759955
J Exp Med. 2000 Mar 6;191(5):771-80
10704459
Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11445-50
11016962
Nature. 1984 Oct 18-24;311(5987):626-31
6090948
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2789-93
1557384
Eur Cytokine Netw. 2000 Jun;11(2):207-15
10903799
Nat Immunol. 2005 Nov;6(11):1142-51
16227984
J Exp Med. 2005 Jan 3;201(1):139-48
15630141
Nat Rev Immunol. 2001 Dec;1(3):200-8
11905829
Cell. 1993 Oct 22;75(2):253-61
8402910
J Immunol. 2006 Nov 1;177(9):6336-43
17056564
J Virol. 1998 Oct;72(10):8264-72
9733870
J Biol Chem. 2007 May 4;282(18):13167-79
17327231
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
8650183
Science. 1987 Oct 2;238(4823):75-8
3116668
Annu Rev Immunol. 1999;17:19-49
10358752