IL-7 Receptor

10 Pages·0.114 MB·English

by  Spits H.

IL-7 Receptor
Hergen Spits
*
Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam,
The Netherlands
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.14003.
SUMMARY ofIL-R(cid:11)and(cid:13)c.Thediscoveryofthislatterreceptor
component is described in the chapter on the IL-2
receptor.
The presently accepted configuration of the func-
tional interleukin 7 (IL-7) receptor is one of a two-
chain receptor consisting of an (cid:11) chain (IL-7R(cid:11)) and Main activities and
a (cid:13) chain ((cid:13) common, (cid:13)c). The latter polypeptide is
pathophysiological roles
denoted (cid:13) common because it is also a component of
the receptors forIL-2, IL-4, IL-9, and IL-15. The IL-
The IL-7R(cid:11) chain plays an essential, nonredundant
7R(cid:11) chain is a member of the cytokine receptor
roleinTandBcelldevelopmentinthemouse(Peschon
superfamily.
et al., 1994) (see also for reviews, Akashi et al., 1998;
TheIL-7R(cid:11)chainplaysanessential,nonredundant
DiSanto and Rodewald, 1998; Maeurer et al., 1998).
role in T and B cell development in the mouse. In
In addition, the IL-7R plays a role in survival
addition, the IL-7R is involved in survival and pro-
and proliferation of functional peripheral T cells
liferationoffunctionalperipheralTcells.TheIL-7R(cid:11)
(Maraskovsky et al., 1996). The IL-7R(cid:11) chain is also
chain is also essential for the formation of Peyer’s
essential for the formation of Peyer’s patches in the
patches in the mouse. In human the IL-7R(cid:11) chain
mouse (Adachi et al., 1998). In humans, the IL-7R(cid:11)
appears to be critical for T but not for B cell devel-
chain appears to be critical for T but not for B cell
opment, as two IL-7R-deficient severe combined
development as two IL-7R-deficient severe combined
immunodeficiency patients presented with B and NK
immunodeficiency patients presented with B and NK
cells but lacked T cells. The receptor has at least two
cells but lacked T cells (Puel et al., 1998).
ligands: IL-7 and TSLP-1. The latter cytokine inter-
actswithacomplexoftheIL-7R(cid:11)chainandanasyet
to be defined receptor distinct from (cid:13)c. GENE
Accession numbers
BACKGROUND
Discovery Human gene: AF043123-9, AF043124-9, AF043125-
9, AF043126-9, AF043127-9, AF043128-9 (these
accession numbers denote the different exons)
The cloning of the IL-7R(cid:11) chain was reported in
Human cDNA: NPI_002185
1990.cDNAclonesencodingthemurine(IL-7)recep-
Mouse cDNA: M29697
tor were isolated from an IL-7-dependent pre-B cell
line (Park et al., 1990) and that for human IL-7R(cid:11)
Chromosome location and linkages
from an SV40-transformed lung cell line (Goodwin
et al., 1990). IL-7R cDNAs expressed in COS-7
cells bound radiolabeled IL-7, producing curvilinear Human IL-7R(cid:11) maps to chromosome 5p13 (Lynch
Scatchard plots containing high- and low-affinity etal.,1992).Thechromosomallocalizationofmurine
classes. The functional receptor for IL-7 is a complex IL-7R(cid:11) is unknown. Human and mouse genes both
1482 Hergen Spits
containeightexonsandsevenintronswithatotalsize conserved extracellular domains fit to bind helical
of 19kb in the human and 24kb in the mouse. The cytokines. IL-7R(cid:11) is similar to other receptors of the
firstexoncontainsthe50 UTR,signalpeptide,andthe (cid:13)cfamilyincluding(cid:13)c,IL-2R(cid:12),IL-4R(cid:11),andIL-9R(cid:11).
N-terminus of the mature protein. The remainder of These are characterized by two fibronectin type III-
theextracellularregionisencodedbyexons2to6.In like domains containing four cysteine residues in the
addition,exon6alsoencodesthetransmembranepart N-terminus domain and a WS motif at the C-
of the cytoplasmic region and exons 7 and 8 encode terminus.HumanandmouseIL-7R(cid:11)arenotspecies-
the rest of the cytoplasmic region. The entire 30 UTR specificasbothmurineandhumanIL-7interact with
is encoded by exon 8. Differential splicing results in human T cells and vice versa.
mRNA encoding a secreted form of the human IL-
7R(cid:11) chain. This form lacks the sequences in exon 6
that encode the transmembrane region. Affinity for ligand(s)
Inspection of the entire 50 region up to the start of
translation of the murine IL-7R(cid:11) revealed a TATA
Reconstitution experiments with human IL-7R(cid:11) and
box and a CAAT sequence. Furthermore an AP-1
(cid:13)c revealed three classes of affinity: an uncharacter-
and an AP-2 sequence were present. Interestingly an
ized low-affinity complex (K =145nM) and com-
interferon response element (IRE)-like sequence was d
plexes of intermediate (K =250pM) and high
found.The50 regioncontainsseveralconsensusbind- d
(K =40pM) affinity. The latter two consist of the
ing sites for the glucocorticoid receptor. The region d
IL-7R(cid:11) alone and complexes of IL-7R(cid:11) and (cid:13)c,
(cid:255)2495 to +5 contains promotor sequences that are
respectively. High-affinity (79pM) and low-affinity
activeinamurinepre-Bcellline(Pleimanetal.,1991).
(16nM) IL-7R were identified on the murine stromal
cell line IxN/2b. Treatment of these cells with anti-(cid:13)c
PROTEIN
antibody reduced the affinity to 255pM without
affecting the low-affinity receptor and the combina-
Accession numbers tion of anti-(cid:13)c plus anti IL-7R(cid:11) eliminated the high-
affinity receptor altogether while the low-affinity
Human: NP_002176 binding was not affected. These findings suggest the
Mouse: AAA39304 existence of a (cid:13)c-independent IL-7R(cid:11)-containing IL-
7 receptor complex (Sugamura et al., 1996). The
nature of the low-affinity complex is unknown but
Description of protein
may involve a yet to be identified receptor
component. The IL-7R(cid:11) chain is also part of the
Murine IL-7R(cid:11) gene encodes a protein of 439 amino
receptor for murine thymus-derived lymphopoietin 1
acids with a calculated molecular weight of 49.5kDa.
(TSLP-1). In the functional TSLP-1R complex IL-
On T cells the protein has a molecular weight
7R(cid:11) does not seem to pair with (cid:13)c but with another
of 90kDa. The associated (cid:13)c chain has a molecular yet to be described receptor (Levin et al., 1999). The
weight of 74kDa. IL-7R(cid:11) is a type I membrane pro-
affinity of this complex for TSLP-1 is unknown.
tein with a single transmembrane domain. The extra-
cellular domain contains features of the cytokine
receptor superfamily. The cytoplasmic domain with
Cell types and tissues expressing
195 amino acids does not contain consensus
sequences of protein kinases. The crystal structure the receptor
oftheIL-7R(cid:11)hasnotbeendetermined.Basedonthe
model of the prolactin receptor, intrachain disulfide See Table 1 (for references in reviews, see Akashi
bridges are most probably formed between the first et al., 1998; DiSanto and Rodewald, 1998; Maeurer
andsecondandbetweenthethirdandfourthcysteine et al., 1998).
residues. The receptor contains a WS motif (WS(cid:2)
WS) at the C-terminus of the extracellular domain.
Release of soluble receptors
Relevant homologies and species
differences
cDNA clones have been isolated that potentially
encode a soluble receptor. These clones lack the
The IL-7R(cid:11) protein is a member of the cytokine sequences in exon 6 encoding the transmembrane
receptor superfamily which is characterized by domain (Pleiman et al., 1991). It has not been
IL-7 Receptor 1483
Table 1 CelltypesandtissuesthatexpresstheIL-7 et al., 1992), in contrast to IL-7R(cid:11)(cid:255)/(cid:255)mice. In
receptor
addition, the phenotype of p56lck(cid:11)(cid:255)/(cid:255) mice is
distinct from that of IL-7R(cid:255)/(cid:255) mice (Molina et al.,
Fetal NK cell/dendritic cell precursors in fetal lymph 1992). Thus, these src kinases do not seem to be
nodes
important in IL-7R signaling. However, an attenuat-
Common T/NK/B lymphoid cell precursors ingroleoftheseenzymesincertainaspectsofIL-7R(cid:11)
Cryptopatch-associated lymphoid precursors signaling cannot be excluded.
Tyrosine kinases belonging to the family of Janus
Developing T cells
kinases are essential for IL-7R signaling. Two Janus
All subsets of CD3(cid:255)CD4(cid:255)CD8(cid:255) thymocytes
kinases,JAK1andJAK3,associatewiththecomplex.
A fraction of CD4+CD8+ DP cells JAK1bindstoIL-7R(cid:11)andJAK3to(cid:13)c(Leonardand
SP CD4+ or CD8+ thymocytes O’Shea, 1998). Both kinases become phosphorylated
when IL-7 binds to its receptor, but the extent of
TCR(cid:13)(cid:14) cells
phosphorylationofJAK3ismuchhigherthanthatof
Thymic NK-1.1+ T cells
JAK1. JAK3(cid:255)/(cid:255) mice have a phenotype similar to
Developing B cells thatofIL-7R(cid:11)(cid:255)/(cid:255)mice(Nosakaetal.,1995;Thomis
All pre-pro, pro-, and pre-B cell stages etal.,1995),stronglysuggestingthatJAK3activityis
required for IL-7R-mediated signaling during T and
Mature T cells
B cell development. In contrast to JAK3, which is
Bone marrow-derived macrophages
specifically expressed in lymphoid cells, JAK1 is
Malignant cell types ubiquitously expressed. Nonetheless, analysis of
Colorectal cancer cells JAK1(cid:255)/(cid:255) mice revealed a dedicated role of JAK1
in T and B cell development (Rodig et al., 1998).
Renal cancer cells
These mice were born but all pups died within 24
Cutaneous T cell lymphomas
hours after birth. The thymus of newborn JAK1(cid:255)/(cid:255)
Human intestinal epithelial cells mice was 260-fold reduced in size as compared with
heterozygous controls. CD4+CD8+ double positive
(DP) cells were present, but the CD4(cid:255)CD8(cid:255) double
negative (DN) compartment was increased. No
reported whether a soluble receptor protein is indeed
further analysis was performed and it is therefore
secreted by cells expressing it. The function of the
unknownwhethertheDNcellsinthethymusofthese
soluble receptor is unknown.
mice were stromal cells or T cell precursors. B cells
were strongly reduced in numbers. Importantly,
whereas wild-type fetal liver cells form colonies in
SIGNAL TRANSDUCTION
IL-3 and IL-7, JAK1(cid:255)/(cid:255) fetal liver cells formed
colonies in IL-3 but not in IL-7 (Rodig et al., 1998).
Associated or intrinsic kinases
These findings demonstrate that JAK1 is an essential
constituent of IL-7R signaling.
The IL-7R complex requires both the (cid:11) chain and (cid:13)c Another kinase that associates with the IL-7R
for relaying signals. These two chains do not have complexisphosphatidyl3-kinase(PI-3kinase).JAK3
intrinsic catalytic activity, but associate with tyrosine appears also to control PI-3 kinase activity (Sharfe
phosphokinases that are instrumental in transducing et al., 1995). PI-3 kinase phosphorylates the D3
signals triggered by binding of IL-7 to the receptor position of the inositol group of phosphoinositide
complex. The src kinase p59fyn has been shown to lipids to generate phosphatidylinositol-3 phosphate
associate with the receptor complex following (PtdIns(3)P), PtdIns(3,4)P and PtdIns(3,4)P
2 3
activation with IL-7 in a human pre-B cell line (KapellerandCantley,1994).Thelattertwoproducts
(Seckinger and Fougereau, 1994). Association of are important for cellular proliferation. The enzyme
p59fyn with the receptor was also found in T cells consists of a 85kDa adapter and a 110kDa catalytic
(Venkitaraman and Cowling, 1992). In both T cells unit. Upon ligand binding the p85 unit is tyrosine
and thymocytes p56lck has been shown to associate phosphorylated and associates with many receptors,
with IL-7R(cid:11). The role of p56lck and p59fyn in IL-7 including the IL-7R(cid:11) chain (Venkitaraman and
signalingisunknown.Fyniscertainlynotessentialin Cowling, 1994). Stimulation of human thymocytes
IL-7R signaling since Fyn(cid:255)/(cid:255) mice have no withIL-7wasshowntoactivatebothisoformsofp85,
reduction in the size of the thymus and numbers of (cid:11) and (cid:12), in human thymocytes (Dadi et al., 1994).
T and B cells in the periphery are normal (Appleby Interestingly,phosphorylationofp85requiredJAK3,
1484 Hergen Spits
which was shown to associate with p85 (Sharfe et al., a downstream effector of PI-3 kinase as well (Pallard
1995). In a later study these authors presented etal.,1999).ThesubstratesofIL-7-activatedPKBare
evidence that two pools of PI-3 kinase are activated not yet known.
by IL-7: one is associated with the IL-7R(cid:11) chain and Two sets of observations suggest a role for the p38
another with insulin receptor substrate 1 (IRS-1) and MAPkinaseinIL-7-mediatedproliferationofmature
IRS-2 (Sharfe and Roifman, 1997). PI-3 kinase T cells. In the first place activation of a murine T cell
appears to be important for survival/proliferation of line by IL-7 resulted in phosphorylation of p38 MAP
both T and B cell precursors. Using human IL-7R(cid:11) kinase and secondly the proliferative response of
mutants transfected into murine pro-B cell lines, human T cells was inhibited by the highly selective
VenkitaramanandCowlingdemonstratedassociation p38 MAP kinase inhibitor SB203580 (Crawley et al.,
ofPI-3kinasewiththeIL-7R(cid:11)chainthroughanSH2 1997). It is unknown which signaling pathway
domain recognition motif (YXXM) spanning residue activates p38 MAP kinase; p21ras is not activated
Tyr449initscytoplasmicdomain(Venkitaramanand by IL-7 and therefore does not act in this pathway.
Cowling, 1994). Interestingly, this residue was found The same report also documented activation of the
to be critical for IL-7-mediated proliferation of stress-activated protein kinase (SAP kinase)/Jun-N-
murine pre-B cells. Induction of IgH VDJ gene terminal kinase(JUN kinase) by IL-7, butthere is no
recombination, however, did not require Tyr449 evidence that activation of this enzyme is important
residue (Corcoran et al., 1996). These findings for the proliferative response induced by IL-7
indicate that IL-7R(cid:11)-transduced signals can control (Crawley et al., 1997). The p38 inhibitor SB203580
both survival and/or proliferation and differentiation influencednegativeselectionthroughtheTCR(cid:11)(cid:12) ina
through distinct pathways. More recently it was fetal thymic organ culture (FTOC) but did not affect
demonstrated that PI-3 kinase also mediates survival thymic cellularity (Sugawara et al., 1998). Since
and proliferation of human T cell precursors. Pallard blocking the IL-7/IL-7R interaction resulted in a
et al. (1999) observed that the Tyr449 in the strong reduction of thymic cellularity and SB203580
cytoplasmic domain of the IL-7R is important for didnot,itisunlikelythatp38MAPkinaseisinvolved
survival and expansion of human thymocytes. A in IL-7-mediated control of early T cell development
dominant negative mutant of p85 that binds to the in the thymus.
receptor but fails to interact with p100, was A potential constituent of the IL-7R signaling is
introduced into human T cell precursors by retro- theserine/threoninekinasepim-1aspro/preBcellsof
virus-mediated gene transfer. This mutant was found pim-1(cid:255)/(cid:255) micedonotproliferate inresponsetoIL-7
to inhibit survival and expansion of the T cell (Domen et al., 1993). Evidence for a direct link
precursors in afetal thymic organculture butdid not between pim-1 and the IL-7R complex is lacking,
inhibit differentiation of these cells. The study of however, since the B and T cell phenotype of pim-1-
Pallard coworkers left unresolved which isoform, deficientmiceiscomparabletothatofwild-typemice.
p85(cid:11) or (cid:12), is recruited by IL-7 binding. These two Itispossiblethattherelatedkinasespim-2andpim-3
isoforms are encoded by different genes. Two recent compensate the pim-1 deficiency, but this has yet to
studiesfailedtoprovideevidenceforaroleofp85(cid:11)in be verified.
T cell development as the size of the thymus and the
distribution of thymocyte subsets was unaffected in
p85(cid:11)(cid:255)/(cid:255) mice (Fruman et al., 1999; Suzuki et al.,
1999). The observation that the level of p85(cid:12) in these DOWNSTREAM GENE
mice is elevated compared with wild-type mice
ACTIVATION
strongly suggests a compensatory role of p85(cid:12) in T
cell development of p85(cid:11)(cid:255)/(cid:255) mice.
Transcription factors activated
Cytoplasmic signaling cascades
In general JAKs phosphorylate the receptor chains,
providing docking sites for SH2 domains of STATs
Recently it was demonstrated that protein kinase B (Leonard and O’Shea, 1998). STATs are recruited to
(PKB) can be activated by IL-7 (Pallard et al., 1999). the phosphorylated sites of the receptor and become
PKB seems to play a central role in PI-3 kinase- phosphorylated. The phosphorylated STATs can
mediatedprotectionagainstapoptosisinawiderange dimerize, translocate to the nucleus and stimulate
of cell types (Coffer et al., 1998). As activation of expression of cytokine-inducible genes. Two studies
PKBaswellasofPI-3kinaserequiresresidueTyr449, documentedactivationofSTAT1byIL-7(Zengetal.,
itisverylikelythatinhumanTcellprecursorsPKBis 1994; van der Plas et al., 1996). The phenotype of
IL-7 Receptor 1485
STAT1-deficient mice, however, makes it unlikely developmentintomatureT cellsinan invitroFTOC.
thatSTAT1playsanessentialroleinIL-7Rsignaling The mutant used by Pallard and coworkers lacks
in vivo as the thymus of these mice is normal and the C-terminal transactivating domain and inhibits
T and B cell development proceeds undisturbed transactivation of wild-type STAT5 and one would
(Meraz et al., 1996). STAT3 and STAT5 have been expect that overexpression of dominant negative
shown to be activated by IL-7 in several cell types STAT5b has the same effect as STAT5 deficiency.
(Leonard and O’Shea, 1998). It is unlikely that There is presently no explanation for these
STAT3 is involvedin IL-7R signaling in vivo. STAT3 discordant effects of the absence of STAT5a and
deficiency results in embryonic lethality preventing STAT5b and of overexpression of dominant negative
analysis of the role of STAT3 in T cell development STAT5b on T cell development. It is possible that
in conventional STAT3(cid:255)/(cid:255) mice. Recently, mice there are species differences in the requirement of
were generated with a STAT3 deficiency specifically STAT5 in murine and human T cell development.
in the T cell lineage by conditional gene targeting Another possibility is that the effect of dominant
using the Cre-loxP system (Takeda et al., 1998). negative STAT5b on development of human T cell
Floxed-STAT3 mice were mated with transgenic precursors is a consequence of a gain of function of
mice with Cre recombinase under control of the T the mutant resulting in activities beyond those of
cell-specific Lck promoter. Although STAT3 was not inhibiting transcription mediated by full-length wild-
expressed in the thymus of these mice, the cellularity type STAT5a or STAT5b.
of the thymus and distribution of thymic subsets was Mel-18 is a mammalian homolog of Drosophila
the same as in control mice (Takeda et al., 1998). melanogaster Polycomb group genes. Mice deficient
ThymocytesofthesemicerespondednormallytoIL-7 for this gene show a severe combined immunodefi-
invitro.Together,thesefindingsindicatethatSTAT3 ciency phenotype with a strongly reduced thymic size
is not involved in IL-7-mediated control of T cell (Akasaka et al., 1997). Thymocytes of these mice fail
development. torespondtoIL-7,suggestinganinvolvementofmel-
IL-7 activates STAT5 in human PBMCs and 18 in cell cycle progression in response to the
thymocytes (Lin et al., 1995; Pallard et al., 1999). interaction of IL-7 and the IL-7R complex.
STAT5 was originally identified as a prolactin-
induced mammary gland transcription factor. Two
STAT5 genes, 5a and 5b, encode proteins that are
Genes induced
approximately 95% identical in amino acid sequence.
STAT5a and STAT5b differ in their C-terminal
transactivation domains and exert relatively specific Presentlytherearenogenesknownthatareprovento
actions.STAT5-deficientmicedisplayimmunological be direct targets of IL-7R-signaling.
defects. STAT5a(cid:255)/(cid:255) mice have a reduced expansion
of peripheral T cells which is associated with a
diminished IL-2-mediated induction of the IL-2R(cid:11)
chain. STAT5b-deficient mice exhibit a reduced BIOLOGICAL CONSEQUENCES
expansion of peripheral NK cells and a slightly
OF ACTIVATING OR INHIBITING
reducedcellularityofthethymus(Imadaetal.,1998).
RECEPTOR AND
In contrast, mice deficient for both STAT5a and
STAT5b were reported to have no major decrease in PATHOPHYSIOLOGY
thymic cellularity (Moriggl et al., 1999). In addition,
the distributions of CD4+, CD8+SP and DP cells Unique biological effects of
were normal, although the number of peripheral T
activating the receptors
cells reduced progressively when these mice aged
(Moriggl et al., 1999). The mechanism of this
reduction is not clear but it is likely that an inability The effects of activation of the IL-7R with IL-7 are
of STAT5-deficient T cells to respond to IL-2 is a discussed in the chapter on IL-7. Disrupting IL-7/IL-
contributing factor. The reported findings on the 7RinteractionsalsoaffecthumanTcelldevelopment.
phenotype of mice deficient for either STAT5a and Antibodies to the human IL-7R(cid:11) strongly inhibited
STAT5b or both argues against a role for STAT5 development of fetal liver and thymic T cell
isoforms in IL-7-mediated control of T cell develop- precursors in a hybrid human/mouse fetal thymic
ment. However, Pallard et al. (1999) reported that organ culture (Plum et al., 1996; Pallard et al., 1999).
overexpression of dominant negative mutant of Development of the human T cell precursors was
STAT5b in human T cell precursors disrupted their arrested at the CD3(cid:255)CD4(cid:255)CD8(cid:255) stage.
1486 Hergen Spits
Phenotypes of receptor knockouts TSLP-1, is involved in T cell development. Support
for this notion comes from the observations that the
and receptor overexpression mice
phenotypeof (cid:13)c- and IL-7-deficient mice is similar to
thatofthe‘mild’IL-7R(cid:11)(cid:255)/(cid:255)mice.AsmurineTSLP-
IL-7R(cid:11)-deficientmicewerereportedbyPeschonetal. 1interactswiththeIL-7R(cid:11)chainina(cid:13)c-independent
(1994).ThesemicehadseverelyreducednumbersofT manner(Levinetal.,1999),aroleofTSLP-1inTcell
andBcells.NKcellnumberswerenotaffectedbythe development could explain why T cell defect in the
IL-7R(cid:11) deficiency and also development of myeloid majority of the IL-7R(cid:11) (exon 3)-deficient mice is
cells was normal. Another IL-7R(cid:11)(cid:255)/(cid:255)mouse was more severe than that in the (cid:13)c(cid:255)/(cid:255) mice. A possible
generated by Ikuta and collaborators (Maki et al., role of TSLP-1 in T cell development has yet to be
1996). In these mice exon 2 was targeted rather than determined.
the exon 3 in the mice generated by Peschon and It is puzzling that the severe phenotype was not
coworkers. The phenotype of these latter mice was found in another, independently generated mouse
similartothatofexon3-targetedmicealthoughsome strain (Maki et al., 1996). In this mouse strain exon 2
differences were noted. was targeted, in contrast to exon 3 that was targeted
Peschon et al. (1998) reported that the T cell in the mice created by Peschon and coworkers. It is
deficiency in IL-7R(exon 3)(cid:255)/(cid:255) mice was variable. difficult to imagine that the differences in targeting
While all IL-7R(cid:11)-deficient mice demonstrated a can be responsible for the phenotypic differences
reduction in thymic cellularity, the level of the between these two mouse strains. However it is clear
reduction varied. In around 65% of the mice the size thatthevariabilityinTcellphenotypeindifferentIL-
of the thymus was only 0.1% of the wild type, while 7R(cid:11)(cid:255)/(cid:255) mice is a complicating factor in the inter-
thethymusoftheothermicewasbetween1and10% pretation of the effect of IL-7R(cid:11) deficiency. As
of the wild type. In the mice with <0.1%, T cell discussed in the chapter on IL-7 IL-7/IL-7R interac-
development was arrested at the CD3(cid:255)CD4(cid:255)CD8(cid:255) tions canbe importantforcell survival, proliferation,
triple negative (TN) CD44+CD25(cid:255) stage with a few and induction of TCR(cid:13) gene rearrangement in T cell
TNCD44+CD25+cells(Figure1),whileinmicewith precursors.
a less severe phenotype all thymic subsets including The IL-7R plays a crucial role in B cell
DP cells were present in normal proportions. development in the mouse. In IL-7R(cid:11)(cid:255)/(cid:255) mice B
IL-7(cid:255)/(cid:255) mice have a phenotype similar to that of cell development is inhibited at the transition of pre-
the ‘less severe’ type of IL-7R(cid:11)(cid:255)/(cid:255) mice. This pro B cells (fraction A) to pro-B cells (Figure 2).
suggests that another IL-7R(cid:11) ligand, for example Inhibition of B cell development in IL-7R(cid:11)(cid:255)/(cid:255) mice
Figure1 Amodelofcellular stagesinTcelldevelopment.Themodelisadaptedfrom
ShortmanandWu(1996)andDiSantoandRodewald(1998).ThestageswhereIL-7and
IL-7R deficiencies affect T cell development are indicated. (cid:3)One of the IL-7R(cid:11)(cid:255)/(cid:255)
strains that was reported by Peschon et al. (1994) showed variability in their thymic
phenotype. Sixty percent had a block in the transition of CD44+CD25(cid:255) to
CD44+CD25+ cells whereas the other 40% had a phenotype comparable to that of
theIL-7(cid:255)/(cid:255)and(cid:13)c(cid:255)/(cid:255)mice.AnotherIL-7R(cid:11)(cid:255)/(cid:255)strainhadaphenotypeidenticalto
that of IL-7(cid:255)/(cid:255) and (cid:13)c(cid:255)/(cid:255) mice (Maki et al., 1996).
TCRgd
IL-7–/–
IL-7Ra –/–1 TCRab +
IL-7Ra –/–1 g c–/– CD4+
CD44+ CD44+ CD44– CD44– CD44– CD4+ CD4+
CD25– CD25+ CD25+ CD25+ CD25– CD8+ CD8+
TCRb + (CD8+) TCRab–
pTa + CD69+ TCRab +
CD8+
g c/IL-7Ra + g c/IL-7Ra +
Responsive to IL-7 Responsive to IL-7
IL-7 Receptor 1487
Figure2 AmodelofearlystagesinmurineBcelldevelopment.Themodelisbased
on observations made by Li et al. (1996). The effects of IL-7 on various B cell
precursor populations are based on information that is summarized in the chapter
and in a review by Maeurer et al. (1998).
IL-7Ra –/– IL-7Ra –/–, g c–/–
Pre-pro-B Early pro-B Late-pro-B Pre-B Immature-B Mature B
Fraction A Fraction B Fraction C Fraction D
CD43+ CD43+ CD43+ CD43– IgM+ IgM+
CD24+ CD24+ CD24+ IgD+
CD19+ CD19+ CD19+
BP-1+ BP-1+
Not Responsive IL-7-responsive. Late pre-B Not
IL-7 responsive to IL-7 + cells do not respond to IL-7 IL-7 responsive
stromal cells
(Peschon et al., 1998) at an earlier stage than in IL- IL-7R(cid:11)(cid:255)/(cid:255) mice. IL-7R(cid:11)+clusters were also absent
7(cid:255)/(cid:255) mice (von Freeden-Jeffry et al., 1998). It is inJAK3(cid:255)/(cid:255)micealthoughsomeIL-7R(cid:11)+cellswere
possible that the alternative IL-7R ligand TSLP-1 foundscatteredovertheintestine.Asdiscussedinthe
plays a role in transition of pre-pro-B cells to pro-B Signaltransductionsection,JAK3isatyrosinekinase
cells and IL-7 in transition of pro-B into pre-B cells. essential for IL-7R signaling and it is therefore clear
Venkitaramanandcoworkershaveshownthatsignals that a signal through the IL-7R(cid:11)/(cid:13)c complex which
through the IL-7R(cid:11) chain are essential for the involves JAK3 is required for the formation of
induction of IgH gene rearrangements and are Peyer’s patches. The observation that (cid:13)c is required
distinct from those that induce proliferation for formation of Peyer’s patches makes it unlikely
(Corcoran et al., 1996). Development of IL-7R(cid:11)(cid:255)/(cid:255) that the IL-7R(cid:11) ligand, TSLP-1, is the factor
B cells could be restored by means of retroviral critical for generation of this organ as TSLP-1 is
transduction of the human IL-7R(cid:11). Mutational thought to act independently of the (cid:13)c chain (Levin
analysis revealed that a single amino acid, Tyr449 et al., 1999).
(see Signal transduction) was required for IL-7-
induced proliferation of the pre-B cells but not for
Human abnormalities
IgH rearrangement. A later analysis of this group
revealed that IL-7 signaling promotes accessibility of
distal V regions to the recombination machinery Two patients have been described who have IL-7R(cid:11)
(Corcoran et al., 1998). The mechanism is yet deficiencies (Puel et al., 1998). These severe combined
unknown but it is of note that IL-7R(cid:11)-deficient immunodeficiency (SCID) patients presented with a
pro-B cells have strongly reduced levels of the profound lack of T cells but with normal numbers of
transcription factor Pax-5, which is important for BandNKcells.Inonepatientthediseasewascaused
IgH V-DJ recombination (Nutt et al., 1998). by two mutations preventing expression of a
A more detailed discussion on the mechanism by functional IL-7R(cid:11); one allele had a splice-junction
which the IL-7/IL-7R(cid:11) interaction controls develop- mutation at the 30 end of intron 4 on one allele and a
ment of various T and B cell subsets can be found in prematurestopcodon(Trp217!stopcodon)inexon
the IL-7 chapter. 5 of the other allele. The disease-causing mutation of
Interestingly,theIL-7Riscriticalfortheformation the second patient is not known. The extracellular
oflymphoidorgansintheintestineasPeyer’spatches domain contained two amino acid changes, but the
are absent in mice deficient for IL-7R(cid:11) and (cid:13)c IL-7R(cid:11) chain derived from this patient bound IL-7
(Adachi et al., 1998). One of the earliest events in the and could transmit signals leading to activation of
formation of Peyer’s patches is the formation of an STAT5. Since the expression of the IL-7R(cid:11) chain in
anlage with VCAM-1+ spots. Clusters of IL-7R(cid:11)+ thesecondpatientwasstronglydiminished,thedefect
cellsareformedsimultaneously.NoVCAM-1+spots in this patient is perhaps localized in the promoter
and clusters of IL-7R(cid:11)+ cells were present in region.
1488 Hergen Spits
With regard to T and B cell development, similar DiSanto,J.P.,andRodewald,H.R.(1998).Invivorolesofrecep-
defects werenotedin patientswithgeneticalterations tor tyrosine kinases and cytokine receptors in early thymocyte
development.Curr.Opin.Immunol.10,196–207.
in the (cid:13)c chain (Noguchi et al., 1993) and JAK3
Domen, J., van der Lugt, N. M., Acton, D., Laird, P. W.,
(Russell et al., 1995). The finding that normal B cells
Linders, K., and Berns, A. (1993). Pim-1 levels determine the
were present in these patients underscores the sizeofearlyBlymphoidcompartmentsinbonemarrow.J.Exp.
dispensability of the IL-7/IL-7R system for develop- Med.178,1665–1673.
ment of B cells in humans. Therefore mice deficient Fruman, D. A., Snapper, S. B., Yballe, C. M., Davidson, L.,
for JAK3, (cid:13)c, or IL-7R(cid:11) are not accurate models for Yu, J. Y., Alt, F. W., and Cantley, L. C. (1999). Impaired B
celldevelopmentandproliferationinabsenceofphosphoinosi-
humans with mutations in these genes.
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