IL-15 Receptor

8 Pages·0.337 MB·English

by  Waldmann Th.A., Tagaya Y.

IL-15 Receptor
Thomas A. Waldmann* and Yutaka Tagaya
Metabolism Branch, National Cancer Institute, NIH Building 10, Room 4N115, 10 Center Drive,
MSC 1374, Bethesda, MD 20892-1374, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14008.
SUMMARY TheIL-2/15R(cid:12)chainandthe(cid:13)cchainweredefined
as part of an analysis of the IL-2 receptor system.
UsingradiolabeledIL-2incrosslinkingstudiesTsudo
IL-15 uses two distinct receptor and signaling
et al. (1986) and Sharon et al. (1986) discovered
pathways. In T and NK cells, the type 1 IL-15
IL-2R(cid:12),a70–75kDabindingsubunit.Grabsteinetal.
receptor includes the IL-2/15R(cid:12) subunit shared with
(1994)andBamfordetal.(1994)usedIL-2R(cid:12)-specific
IL-2,the(cid:13)csubunitsharedwithIL-2,IL-4,IL-7,and
antibodies to demonstrate that IL-15 requires this
IL-9, as well as an IL-15-specific receptor subunit
subunit for its action in T and NK cells. Takeshita
IL-15R(cid:11). Thus type 1 receptor uses a JAK1/JAK3
et al. (1992) defined and cloned the (cid:13)c receptor and
and STAT3/STAT5 signaling system. Mast cells
showed thatit wasacomponentofthe IL-2receptor.
respond to IL-15 with a type 2 receptor system that
It was subsequently demonstrated that IL-2R(cid:13) (now
does not share elements with IL-2R but uses a novel
termedcommongammaor(cid:13)c)isnotonlyanessential
60–65kDa IL-15RX subunit. This type 2 receptor
element of high- and intermediate-affinity receptors
signaling involves JAK2/STAT5 activation. In addi-
for IL-2, but is also required for the actions of IL-4,
tion to the other functional activities in immune and
IL-7, and IL-9 (Kondo et al., 1993; Noguchi et al.,
nonimmune cells, signaling through the type 1 IL-15
1993). Giri et al. (1994) demonstrated in cells trans-
receptor plays a pivotal role in the development,
fected with IL-2R subunits that (cid:13)c as well as IL-2R(cid:12)
survival, and activation of NK cells.
are required for IL-15 binding and signaling. IL-15
does not use the (cid:11) subunit of the IL-2 receptor.
However, a novel IL-15-specific binding protein
BACKGROUND termed IL-15R(cid:11) was identified and its cDNA cloned
byGirietal.(1995).ThusinTandNKcellstheIL-15
Discovery
Figure 1 IL-15 receptors.
IL-15 is a 14–15kDa member of the four (cid:11) helix
bundlefamilyof cytokines.IL-15 utilizes two distinct
receptor and signaling pathways (Figure 1). In T and Type 1 (T/NK cells) Type 2 (Mast cells)
NK cells the type 1 IL-15 receptor includes the (cid:13)c
IL-15 IL-15
sharedwithIL-2,IL-4,IL-7,IL-9,andtheIL-2/15R(cid:12)
subunitsharedwithIL-2.Furthermore,itinvolvesan
IL-15-specificreceptorsubunit,IL-15R(cid:11).Incontrast, IL-15 IL-2 g IL-15 ?
mast cells respond to IL-15 using a receptor system Ra 15Rb c RX
that does not share elements with the IL-2R system
but involves a novel 60–65kDa IL-15RX subunit.
JAK2
JAK1 JAK3
In mast cells IL-15 signaling involves JAK2 and
STAT5 activation rather than the JAK1/JAK3 and STAT5
STAT3 STAT5
STAT3/STAT5 that are used by IL-15 in activated
T and NK cells. IL-15 receptors
1522 Thomas A. Waldmann and Yutaka Tagaya
receptor was shown to involve an IL-15-specific IL-15 acting through the type 2 receptor stimulates
subunit IL-15R(cid:11), the IL-2/15R(cid:12) subunit shared with mast cells proliferation. IL-15 also acts on skeletal
IL-2,andthe(cid:13)csubunitsharedwithIL-2,IL-4,IL-7, muscle (Quinn et al., 1997), endothelial cells, and
and IL-9. Tagaya et al. (1996a,b) demonstrated that microglia (Lee et al., 1996; Hanisch et al., 1997).
IL-15 uses a distinct type 2 receptor/signal trans-
ductionpathwayin mastcells. Mastcells were shown
to respond to IL-15 with a receptor system that does
GENE
not share elements with the IL-2R but uses a novel
60–65kDa IL-15RX subunit.
Accession numbers
Alternative names
GenBank:
Human IL-15R(cid:11): NM_002189
The (cid:12) chain shared by IL-2 and IL-15 is frequently Human IL-2/15R(cid:12): NM_000878
calledIL-2R(cid:12).ItisalsoreferredtoasIL-2/15R(cid:12).The Human (cid:13)c: NM_000206
common gamma chain, (cid:13)c, was initially termed IL- Mouse IL-15R(cid:11): U22339
2R(cid:13) prior to the demonstration of its use by other Mouse IL-2/15R(cid:12): M28052
cytokines. The IL-15-specific receptor in T and NK Mouse (cid:13)c: U21795
cellsistermedIL-15R(cid:11),whereasthechaininvolvedin
the type 2 receptor of mast cells is IL-15RX.
Sequence
Structure
NucleotidesequencesfortheIL-15Rcomponentscan
be found in GenBank. The accession numbers are
IL-2/15R(cid:12) and (cid:13)c are members of the cytokine I shown above.
superfamily of receptors that contain four conserved
cystines and the canonical WSXWS (Trp-Ser-X-Trp-
Ser) motif. IL-15R(cid:11) is a type 1 membrane protein
Chromosome location and linkages
that is not a member of the cytokine receptor
superfamily. However, a comparison of IL-2R(cid:11) and
IL-15R(cid:11) revealed the shared presence of a conserved Human (cid:11): 10 p15-14; (cid:12): 22q11.2-q12; (cid:13)c: Xq13
motif known as the GP-1 motif or a SUSHI domain Mouse (cid:11): 2; (cid:12): 15: (cid:13)c: X
(Girietal.,1995).Thestructureofthemastcelltype2 The chromosomal localization of IL-15RX has not
IL-15RX receptor subunit has not been defined. been defined.
Main activities and Relevant linkages
pathophysiological roles
IL-15R(cid:11) and IL-2R(cid:11) are linked in humans on
Through its action on its receptor, IL-15 stimulates chromosome10p15-14andinmiceonchromosome2
the proliferation of activated CD4(cid:255)CD8(cid:255), CD4+ (Anderson et al., 1995).
CD8+, CD4+ and CD8+ cells, and dendritic epi-
dermal T cells (Burton et al., 1994; Grabstein et al.,
1994; Edelbaum et al., 1995; Garcia et al., 1998). It
PROTEIN
was recently reported that IL-15 preferentially pro-
pagates CD8 memory T cells (Zhang et al., 1998).
Accession numbers
Although IL-15 does not have an effect on resting
B cells it induces proliferation and immunoglobulin
synthesis by B cells costimulated by PMA or by Human IL-15R(cid:11): NP_002180
an immobilized antibody to immunoglobulin M Human IL-2/15R(cid:12): NP_000869
(Armitage et al., 1995). Human (cid:13)c: NP_000197
One of the most critical functions of IL-15 acting Mouse IL-15R(cid:11): AAC52240
through the type 1 receptor is a pivotal role in the Mouse IL-2/15R(cid:12): AAA39283
development, survival, and activation of NK cells. Mouse (cid:13)c: AAA64279
IL-15 Receptor 1523
Sequence motif. IL-15RX is a 60–65kDa receptor whose
structure has not been defined.
See Figure 2.
Relevant homologies and
species differences
Description of protein
IL-2/15R(cid:12) and (cid:13)c are members of the hematopoietin
or cytokine superfamily of receptors. IL-15R(cid:11) shares
IL-15R(cid:11) is a type 1 membrane protein with a
with IL-2R(cid:11) the presence of the GP-1 or SUSHI
predicted signal peptide of 32 amino acids, a
domain motif. Furthermore, the IL-2R(cid:11) and IL-
173 amino acid extracellular domain, a single
15R(cid:11) genes have a similar intron–exon organization.
membrane-spanning region of 21 amino acids, and a
Moreover, they are closely linked on both human
37aminoacidcytoplasmicdomain(mouseIL-15R(cid:11)).
(10p-15-14) and murine genomes (chromosome 2)
In contrast to IL-2/15R(cid:12) and (cid:13)c, IL-15R(cid:11) is not a
(Anderson et al., 1995).
member of the cytokine receptor superfamily.
However, IL-15R(cid:11) contains a motif known as a
Affinity for ligand(s)
GP-1 motif or a SUSHI domain (Giri et al., 1995).
The human IL-2/15R(cid:12) mRNA encodes a primary
translation product of 551 amino acids (Hatakeyama IL-15R(cid:11) binds IL-15 with a very high affinity
et al., 1989). The receptor contains a 26 amino acid (dissociation constant K (cid:136)10(cid:255)11M) (Anderson
d
signal peptide and a mature human IL-2/15R(cid:12) is et al., 1995; Giri et al., 1995). This affinity was not
composed of 525 amino acids with an extracellular dramatically altered by the simultaneous presence of
segment of 214 amino acids, a hydrophobic trans- IL-2/15R(cid:12)or(cid:13)c.IL-2/15R(cid:12)and(cid:13)cactingtogetherin
membranestretchof25aminoacids,anda286amino the absence of IL-15R(cid:11) bind IL-15 with an
acid cytoplasmic domain. The human (cid:13)c cDNA intermediate affinity (approximately K (cid:136)10(cid:255)9M).
d
containsanopenreadingframeencodinga369amino IL-15RX binds IL-15 with an intermediate affinity
acidresiduepolypeptide(Takeshitaet al.,1992).This (K (cid:136)10(cid:255)9M) (Tagaya et al., 1996b).
d
proteincontainsa22aminoacidsignalpeptide,a233
amino acid extracellular domain, a 28 amino acid Cell types and tissues expressing
hydrophobic transmembrane domain, and an 86
the receptor
amino acid terminal cytoplasmic domain. IL-2/15R(cid:12)
and(cid:13)caremembersofthehematopoietinorcytokine
superfamily of receptors that contain four conserved IL-15R(cid:11) has a wide cellular distribution. Its expres-
cystines and canonical WSXWS (Trp-Ser-X-Trp-Ser) sion is observed in T cells, B cells, macrophages, and
Figure 2 The amino acid sequences for human IL-15R(cid:11) (Anderson et al.,
1995) and mouse IL-15R(cid:11) (Giri et al., 1995). The transmembrane domain is
underlined.
1524 Thomas A. Waldmann and Yutaka Tagaya
in thymic stroma cells and bone marrow stroma cells tyrosine kinases p56lck and p72syk, the induction of
(Andersonetal.,1995).Inaddition,IL-15R(cid:11)mRNA theexpressionoftheBcl-2anti-apoptoticproteinand
is widespread in such tissues as liver, heart, spleen, the stimulation of the Ras/Raf/MAP kinase pathway
lung,skeletalmuscle,andactivatedvascularendothe- leading to fos/jun activation (Miyazaki et al., 1995).
lial cells (Giri et al., 1995). IL-15R(cid:11) mRNA is Mast cells respond to IL-15 with a type 2 receptor
increased in T cells after addition of IL-2, an anti- systemthatusesanovel60–65kDaIL-15RXsubunit.
CD3 antibody or phorbol-myristate acetate (PMA) Thistype2receptorinvolvesJAK2/STAT5activation
(Giri et al., 1995). Furthermore, IL-15R(cid:11) expression rather than the JAK1/JAK3 and STAT3/STAT5
is augmentedin macrophagecell lines aftertreatment system used by the type 1 receptor in T/NK cells.
with IFN(cid:13). IL-2/15R(cid:12) is constitutively expressed by
NKcells,monocytes,andrestingCD8cellsbutisnot
expressedbyrestingCD4cellsalthoughitisinducible DOWNSTREAM GENE
in such cells. The common gamma chain is expressed
ACTIVATION
by most hematopoietic cells.
Transcription factors activated
Regulation of receptor expression
IL-15 through the type 1 receptor activates jun/fos
IL-2/15R(cid:12): Promoter/enhancer region contains puta- AP-1complex.ItalsoactivatesSTAT3,STAT5a,and
tive binding sites for Ets-1, GABP, SP-1 and Egr-1 STAT5b transcription factors (Lin et al., 1995).
(Lin and Leonard, 1997). The type 2 receptor signaling activates STAT5a
(cid:13)c: The (cid:13)c gene has a constitutive activation and b molecules.
promoter that contains an Ets-binding site.
IL-15R(cid:11): The 50 regulatory region of this gene is
Genes induced
not defined.
The genes induced by IL-15R include IL-2R(cid:11)
Release of soluble receptors (Treiber-Held et al., 1996), CC chemokines and
receptors (Perera et al., 1999), bcl-2/bcl-X anti-
L
apoptotic genes, caspase 8/FLICE (Perera and
In contrast to the release of IL-2R(cid:11), there is little
Waldmann, 1998), Pim-1, CIS/SIS/SOCS family
release of IL-2/15R(cid:12) or (cid:13)c. Although levels have not
member proteins, and c-myc.
been quantitated, it has been suggested that IL-15R(cid:11)
isreleasedfromthecellsurfaceandmayacttoinhibit
IL-15 action. Promoter regions involved
The promoter regions involved are the STAT5
SIGNAL TRANSDUCTION
consensus sequence and AP-1 sites.
Associated or intrinsic kinases
BIOLOGICAL CONSEQUENCES
The type 1 IL-15 receptors in T and NK cells, like
OF ACTIVATING OR INHIBITING
most cytokine receptors, do not possess intrinsic
RECEPTOR AND
protein tyrosine kinase (PTK) domains, yet receptor
stimulation invokes rapid tyrosine phosphorylation PATHOPHYSIOLOGY
of intracellular proteins including the receptors
themselves. In T and NK cells, IL-15 activates Unique biological effects of
JAK1 and JAK3 of the tyrosine kinase family
activating the receptors
members (Witthuhn et al., 1994; Johnston et al.,
1995). Furthermore, the addition of IL-15 to such
receptor-expressing T cells led to the tyrosine phos- For more detail on the biological effects of IL-15
phorylationandnucleartranslocationofSTAT3and receptor, see the review by Waldmann and Tagaya
STAT5 (Johnston et al., 1995; Lin et al., 1995). The (1999).
IL-15-signaling pathway in T cells also involves the IL-15 actingthroughthe type1receptor stimulates
phosphorylation of the Src-related cytoplasmic the proliferation of activated CD4(cid:255)CD8(cid:255), CD4+
IL-15 Receptor 1525
CD8+, CD4+, and CD8+ cells (Burton et al., 1994; anemia (Suzuki et al., 1997). These animals mani-
Grabstein et al., 1994; Edelbaum et al., 1995; Zhang fested marked infiltrative granulopoiesis and died
et al., 1998; Garcia et al., 1998). IL-15 also has an after about 12 weeks. The (cid:13)c chain is shared by IL-2,
effect on activated but not resting T cells, inducing IL-4,IL-7,IL-9,andIL-15;thusmicedeficientinthis
proliferation and immunoglobulin synthesis in cells chain lack the ability to respond to all of these
costimulatedbyPMAorbyanimmobilizedantibody cytokines. Mice made deficient in this cytokine or its
to IgM (Armitage et al., 1995). IL-15 may be an membrane-proximal signaling element, JAK3, man-
essential factor for the development of NK cells ifest severe combined immunodeficiency disease with a
(Carson et al., 1994). NK cells are absent in mice virtual absence of NK cells markedly deficient T cell
made deficient in elements required for IL-15 action, numbers and function and abnormalities of B cell
including IL-2/15R(cid:12) (Suzuki et al., 1997), (cid:13)c (Cao function,presumablyduetothelackofIL-7function
et al., 1995; DiSanto et al., 1995), IRF-1(cid:255)/(cid:255) in early T/B cell development.
(Ogasawara et al., 1998; Ohteki et al., 1998), JAK3
(Biron et al., 1989; Russell et al., 1995; Macchi et al.,
1995), or STAT5a/b (Imada et al., 1998; Teglund Human abnormalities
et al., 1998). Furthermore, IL-15 is effective in
inducingbonemarrowprogenitordifferentiationinto
No patients with deficiency of IL-15R(cid:11), IL-2/15R(cid:12),
NKcells(Mro´zeketal.,1996;Cavazzana-Calvoetal.,
or IL-15RX have been defined. Patients deficient in
1996). In a similar way, the addition of IL-15 to
(cid:13)c manifest X chromosome-linked severe combined
immature postnatal thymocytes or to fetal thymic
immunodeficiency disease (X-SCID) (Schorle et al.,
organ cultures led to the development of NK cells
1991; Noguchi et al., 1993). Patients with this dis-
(Mingari et al., 1997).
order have a dramatic reduction in T and NK cells
IL-15 also has unique functions on nonlymphoid
but have at least normal numbers of B cells that
cells. Acting through the type 2 receptor it stimu-
are functionally abnormal. Deficiency of JAK3 in
lates mast cell proliferation (Tagaya et al., 1996a,b).
humans yields an autosomal disorder with the same
Although the type of receptor has not been defined,
phenotype.
IL-15 also has actions on muscle, inducing skeletal
muscle fiber hypertrophy (Quinn et al., 1997),
vascular endothelial cells promoting angiogenesis
THERAPEUTIC UTILITY
(Angiolillo et al., 1997), and on brain microglia
and astrocytes(Lee et al., 1996;Hanisch et al.,1997).
Effect of treatment with soluble
receptor domain
Phenotypes of receptor knockouts
and receptor overexpression mice The injection of an IL-15 antagonist with the soluble
form of IL-15R(cid:11) into DBS/1 mice suppressed their
development of collagen-induced arthritis (Ruchatz
IL-15R(cid:11)-null (IL-15R(cid:11)(cid:255)/(cid:255)) mice are markedly lym-
et al., 1998).
phopenic despite grossly normal T and B lymphocyte
development(Lodolceetal.,1998).Thislymphopenia
is due to decreased proliferation and decreased Effects of inhibitors (antibodies) to
homing of IL-15R(cid:11)(cid:255)/(cid:255) lymphocytes to peripheral
receptors
lymph nodes. These mice are also deficient in NK
cells, natural killer T cells, CD8+ lymphocytes, and
TCR(cid:13)/(cid:14)-intraepithelial lymphocytes. In addition, An IL-15 receptor antagonist has been produced by
memory phenotype CD8+ T cells are selectively mutatingglutamineresidueswithintheC-terminusof
reduced in number. IL-15 to aspartic acid, completely inhibiting IL-15-
Mice lacking the IL-2/15R(cid:12) chain are deficient in triggered cell proliferation (Kim et al., 1998). This
functions mediated by either IL-2 or IL-15 since this IL-15 mutant protein markedly attenuated antigen-
receptor is shared by these two cytokines. Mice specific delayed hypersensitivity responses in Balb/c
lackingthisreceptorlackNKcells.Furthermore,they mice and enhanced the acceptance of islet cell
manifest spontaneously activated T cells, increased allografts. An antibody (Mik(cid:12)1) directed toward
differentiation of B cells into plasma cells, and high IL-2/IL-15R(cid:12) inhibits the actions of IL-15 but not
serum concentrations of immunoglobulins IgG and thosemediatedbyIL-2throughthehigh-affinityIL-2
IgE as well as autoantibodies that cause hemolytic receptor. A humanized version of this antibody
1526 Thomas A. Waldmann and Yutaka Tagaya
prolonged renal allograft survival in cynomolgus DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A., and
monkeys (Tinubu et al., 1994). Rajewsky, K. (1995). Lymphoid development in mice with a
targeted deletion of the interleukin 2 receptor (cid:13) chain. Proc.
The clinical application of new therapeutic agents
NatlAcad.Sci.USA92,377–381.
that target IL-15 or the receptor and signaling ele-
Edelbaum, D., Mohamadzadeh, M., Bergstresser, P. R.,
ments shared by IL-15 and other T cell stimula- Sugamura, K., and Takashima, A. (1995). Interleukin (IL)-15
tory cytokines may provide a new perspective for promotesthegrowthofmurineepidermalgammadeltaTcells
the treatment of tropical spastic paraparesis HTLV-I- byamechanisminvolvingthebeta-andgammac-chainsofthe
IL-2receptor.J.Invest.Dermatol.105,837–843.
associated myelopathy (TSP/HAM), rheumatoid
Garcia, V. E., Jullien, D., Song, M., Uyemura, K., Shuai, K.,
arthritis,andinflammatoryboweldiseasewhereabnor-
Morita, C. T., and Modlin, R. L. (1998). IL-15 enhances the
malities of IL-15 expression have been demonstrated. responseofhumangammadeltaTcellstononpeptidemicrobial
antigens.J.Immunol.160,4322–4329.
Giri, J. G., Ahdieh, M., Eisenman, J., Shanebeck, K.,
Grabstein, K., Kumaki, S., Namen, A., Park, L. S.,
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LICENSED PRODUCTS
Liew,F.Y.(1998).SolubleIL-15receptoralpha-chainadmin-
istration prevents murine collagen-induced arthritis: a role for
IL-15 in development of antigen- induced immunopathology. ApolyclonalantibodyagainsthumanandmurineIL-
J.Immunol.160,5654–5660.
15R(cid:11) peptide may be obtained from Santa Cruz
Russell, S. M., Tayebi, N., Nakajima, H., Riedy, M. C.,
Biotechnology Inc., Santa Cruz, CA, USA.
Roberts, J. L., Aman, M. J., Migone, T. S., Noguchi, M.,
Markert, M. L., Buckley, R. H., O’Shea, J. J., and
Antibodies against human IL-2/15R(cid:12) molecule
Leonard, W. J. (1995). Mutation of Jak3 in a patient with
Mik(cid:12)2 and (cid:12)3 monoclonal antibodies are available
SCID: essential role of Jak3 in lymphoid development.
Science270,797–800. from PharMingen (San Diego, CA, USA).
1528 Thomas A. Waldmann and Yutaka Tagaya
Polyclonal antibodies against IL-2/15(cid:12) peptides are Antibodies against human (cid:13)c molecule
available from Santa Cruz Biotechnology (Santa A monoclonal anti-human (cid:13)c antibody is available
Cruz, CA, USA). from PharMingen.
Antibodies against murine IL-2/15R(cid:12) molecule Antibodies against murine (cid:13)c molecule
Two monoclonal anti-murine IL-2/15R(cid:12) antibodies Monoclonal antibodies recognizing the murine (cid:13)c
may be obtained from PharMingen. Santa Cruz molecule are available from PharMingen.
carriesanti-mouseIL-2/15R(cid:12)polyclonalIgGsthatare Polyclonal anti-mouse (cid:13)c peptides are available from
raised against synthetic peptides from this molecule. Santa Cruz Biotechnology.