4-1BB

6 Pages·2006·0.103 MB·English

by  Vinay D.S., Kwon B.S.

4-1BB
Dass S. Vinay1 and Byoung S. Kwon2,3,*
1Department of General Surgery, University of Michigan Medical School, 1516 MSRB I, 1150 West
Medical Center Drive, Ann Arbor, MI 48109, USA
2The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea
3Department of Ophthalmology, LSUMC, 2020 Gravier Street Suite B, New Orleans, LA 70112, USA
*corresponding author tel: [phone] ext 1379, fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.16007.
SUMMARY especially when stimulus through TCR is acute, 4-
1BB can replace CD28 in the costimulation of naı¨ve
T cells (Watts and DeBenedette, 1999).
4-1BB (CD137) is a member of the tumor necrosis
The molecular basis underlying 4-1BB-mediated
factor (TNF) receptor superfamily expressed on acti-
T cell activation is beginning to be appreciated.
vated CD4+, CD8+, as well as on NK cells (Vinay
Althoughexhaustivestudiesarelacking,theavailable
and Kwon, 1998). 4-1BB binds to 4-1BB ligand (4-
datashowthatthisTcell-activatingantigentransmits
1BBL) found on activated B cells, macrophages, and
signals via interactions with the TNF receptor-
dendritic cells (Alderson et al., 1994; Goodwin et al.,
associated (TRAF) family of molecules, such as
1993; Pollok et al., 1994; DeBenedette et al., 1997).
TRAF1, TRAF2, and TRAF3, and activates NF(cid:20)B
Data accumulated thus far show that signals gen-
(Saoulli et al., 1998;Arch and Thompson, 1998;Jang
erated through 4-1BB induce T cell activation and
et al., 1998).
cytokine modulation (Vinay and Kwon, 1998). These
observationsarefurthersubstantiatedbythefindings
that 4-1BBL-expressing cell lines or soluble 4-1BBL
induce T cell proliferation and IL-2 secretion
BACKGROUND
(Goodwin et al., 1993; DeBenedette et al., 1995,
1997; Hurtado et al., 1995; Saoulli et al., 1998). Also,
the finding that addition of 4-1BB fusion proteins Optimal induction of T cell activation is incomplete
block T cell proliferation mediated by 4-1BBL without cognate interaction between T cells and
(Goodwin et al., 1993; DeBenedette et al., 1995, antigen-presenting cell (APC)-derived cell surface
1997;Hurtadoetal.,1995;Saoullietal.,1998)further molecules(Schwarz,1990).AnumberofAPC-derived
support a strong role for 4-1BB in T cell regulation. cell surface determinants have been shown to possess
Evidence gathered also points out that antibodies to the ability to potentiate/desensitize T cell effector
4-1BB possess an increasing ability to activate and functions. Although it is considered that B7/CD28 is
control CD8 responses (Shuford et al., 1997; Melero central to this pathway, studies of CD28-deficient
et al., 1997). This fact is further evidenced by recent mice(Shahnianetal.,1993)haveshownthatthismay
findings using 4-1BBL-deficient mice (DeBenedette not be the limiting factor in immune regulation.
et al., 1999; Tan et al., 1999). Interestingly, litera- Recent studies indicate that several ligand/receptor
ture also points out a role for 4-1BB in TH1 (Kim pairs, beyond the B7/CD28 pathway, also have the
et al., 1998) and TH2 (Chu et al., 1997) and TC1 and ability to initiate and propel the ongoing immune
TC2development(VinayandKwon,1999).Although, reaction. Among these are three members of the
CD28 is considered as central to the T cell immune expanding TNFR family: 4-1BB, Ox40, and GITR
responses (Chambers and Allison, 1997), evidence that may be involved in T cell function in the post
available demonstrates that during T cell activation, CD28 phase.
1686 Dass S. Vinay and Byoung S. Kwon
Discovery Figure 1 Organization of the 4-1BB gene. Exons are
shownasboxes;UTRsaredisplayedasredboxeswhile
the protein-coding regions are green boxes (Roman
TheT cell-activating antigen (Ag)4-1BB wasinitially
numerals). Lengths of exons and introns are shown in
discovered in screens for receptors on activated
Arabicnumerals(basepairs).(Fullcolourfiguremaybe
mouse lymphocytes (Kwon and Weissman, 1989).
viewed online.)
Alternative names Exon I Exon I Exon II
4-1BB was originally named ‘induced by lymphocyte
activation’ (ILA) in humans and 4-1BB in the mouse Exon IV Exon V
(Pollok et al., 1993; Schwarz et al., 1993). Both ILA
and 4-1BB recently received the human leukocyte
differentiation antigen (HLDA) nomenclature Exon VI Exon VII Exon VIII Exon IX
CD137.
Structure
4-1BB is a 30kDa glycoprotein and exists both as a
andserine,threonine,proline(STP)-richregionimme-
monomer and a 55kDa dimer on the T cell surface.
diately outside the transmembrane domain are con-
The entire gene spans approximately 13kb of mouse
tained in separate exons. Finally, the cytoplasmic
chromosome 4.
domain that contains the p56lck-binding site is
located in the last exon of the gene. The exon/intron
Main activities and boundaries are assigned by comparing the 4-1BB
cDNA sequence with the genomic sequence. In the
pathophysiological roles
flanking sequence of the type I 50 UTR, no TATA
box-related elements were found. Instead, they are
4-1BB is shown to transmit costimulatory signals to very good matches of the consensus TPA-responsive
T cells in synergy with anti-CD3. Functional studies element (AP-1) at positions (cid:255)18 to (cid:255)10, and of the
reveal that antibodies to the 4-1BB molecule can NF(cid:20)B-binding sequence at positions (cid:255)49 to (cid:255)39.
increase graft-versus-host disease, accelerate the rejec- Upstream of these elements, this region contains a
tion of cardiac allografts and skin transplants, and potential ets-binding site at positions (cid:255)169 to (cid:255)162,
eradicate established tumors. 4-1BB is also known to an activator protein 2 (AP-2)-binding site at posi-
play an important role in HIV and Hodgkin’s disease tions (cid:255)460 to (cid:255)453, a typical CAAT element at
(see Vinay and Kwon, 1998 for a review). positions (cid:255)498 to (cid:255)494, and an SP-1-binding site at
positions (cid:255)522 to (cid:255)516.
The 5’ flanking region of the type II 50 UTR
GENE
contains a TATA-related element at positions (cid:255)28 to
(cid:255)23. Two potential ets-binding sites appear at posi-
Accession numbers tions (cid:255)15 to (cid:255)8 and (cid:255)139 to (cid:255)132, two potential
AP-2-bindingsitesatpositions(cid:255)89to(cid:255)82and(cid:255)331,
U022567 and a very good match of an AP-1-binding site at
positions (cid:255)311 to (cid:255)302.
Sequence
PROTEIN
The 4-1BB gene consists of 10 exons and 9 introns in
which there are two exons for 50UTR and 8 for the Accession numbers
codingregion(Figure1).TwotypesofUTRsequences
were identified in the genomic sequence and found to Murine 4-1BB: J04492
beseparatedbyanintron(cid:24)2.5kbinlength.Thecys- Human 4-1BB: U03397
teine-rich extracellular domain is divided into six Mouse 4-1BB ligand: L15435
exons. The signal sequence, transmembrane region, Human 4-1BB ligand: U03398
4-1BB 1687
Description of protein with a K of 1.86nM. Western analysis showed
d
that 4-1BBL has a molecular mass of approximately
18–25kDa.
The nucleotide sequence of murine 4-1BB revealed a
single open reading frame which codes for a poly-
peptide of 256 amino acids with a calculated mass of Cell types and tissues expressing
27,587Da. The predicted protein contained an
the receptor
unusually large number (23) of cysteines. This region
comprises four potential TNFR motifs, of which the
The 4-1BB molecule is present on activated T cells
first is partial and the third distinct from those of the
and monocytes.
TNFR.
Following this ligand-binding domain is a stretch
of amino acids (residues 140–185), in which almost Regulation of receptor expression
30% of the amino acids are serine and threonines;
potential sites for O-linked glycosylation. Amino
The 4-1BB is not detected (<3%) on resting T cells
acids 186–211 constitute the hydrophobic transmem-
and T cell lines. However, when the T cells, in the
brane domain followed by the stop-transfer sequence
presence of APCs, stimulated with a variety of
containingseveralbasicresidues.TheC-terminalpart
agonists (plate-bound anti-CD3, Con A, PHA, IL-2,
ofthecytoplasmicdomaincontainstwoshortrunsof
IL-4, anti-CD28, PMA, ionomycin alone or in com-
three and four acidic residues, respectively, and a
binations) upregulates and maintain its expression
sequence of five glycines followed by a tyrosine.
(Pollok et al., 1993). Upon activation, 4-1BB mRNA
The human homolog of 4-1BB (h4-1BB) contains
is detected within hours and cell surface expression
255 amino acids with two potential N-linked glyco-
can be detected between 10 and 16 hours. The
sylation sites. The molecular weight of its protein
expression peaks at 64 hours and is maintained until
backbone is calculated to be 27kDa (Zhou et al.,
120 hours after single stimulation (Hurtado et al.,
1995) and is 60% identical to mouse 4-1BB. In the
1995).Interestingly,expressionof4-1BBisdetectable
cytoplasmic domain, five regions of amino acid
on T cells derived from individuals with pathological
sequences are conserved between mouse and human,
conditions (Michel et al., 1998) indicating that its
indicatingthattheseresiduesmightbeimportantin4-
expression is indeed activation dependent.
1BB function.
Affinity for ligand(s) Release of soluble receptors
Although the h4-1BB ligand was detected in both One of the interesting aspects of 4-1BB in immune
T and B cells of human peripheral blood, the ligand regulation is its ability to occur in soluble form in
was preferentially expressed in primary B cells and tissue microenvironment. The 4-1BB shares this
Bcelllines.Daudi,aBcelllymphoma,wasoneofthe feature with certain other receptor forms like
B cell lines that carried a higher number of ligands. TNFR, NGFR, CD27, CD30, and CD95. Evidence
Scatchard analysis showed that the K (cid:136)1.4(cid:2)109M documentedtillnowsuggeststhatthe4-1BBmolecule
d
and the number of ligands in Daudi cells was 4.2(cid:2) is secreted in soluble form in sera and lymphocyte
103. Primary B cells when stimulated with pokeweed secretions in patients with rheumatoid arthritis (for
mitogen showed enhanced ligand expression receptor details, see Michel et al., 1998). The significance of
binding. On the other hand, the ligand for murine 4- such a phenomenon remains to be explored.
1BB (m4-1BBL) can be found at low levels on T cell
lines (nonactivated and anti-CD3-activated), pre-B
SIGNAL TRANSDUCTION
cell lines and a few immature macrophage cell lines.
Also, the binding analysis with 4-1BB AP (a fusion
Associated or intrinsic kinases
protein consisting of the extracellular domain of 4-
1BB fused to human placental alkaline phosphatase)
exhibited no binding to glial tumor cell line, HeLa Though not studied in detail, the signal transduction
cells, or COS cells. On the other hand, the anti-IgM- pathways chosen by 4-1BB is beginning to be appre-
activated primary B cells compared with anti-CD3- ciated. Studies carried out thus far suggest that no
activated primary T cells showed higher binding of apparent kinase activity is observed with 4-1BB,
4-1BBAP.ScatchardanalysisindicatedthattheA20 suggesting that 4-1BB-associated molecules may be
B cell lymphomaexpressed3680 bindingsites percell involved in 4-1BB-mediated signal transduction.
1688 Dass S. Vinay and Byoung S. Kwon
Cytoplasmic signaling cascades the cytolytic capacity of IL-2-activated intestinal
intraepithelial cells (IELs) (Zhou et al., 1994).
Our laboratory recently provided evidence that 4-
Available data indicate that, like its relatives in the
1BB may be involved in the pathogenesis of AIDS.
TNFR superfamily, signals by 4-1BB are relayed
The level of 4-1BB expression and the percentage of
through TNF receptor-associated factors (TRAFs).
4-1BB-expressing T cells were higher in HIV-1-
Studies from our lab found that TRAF1, TRAF2,
positive individuals than in HIV-1-negative controls
and TRAF3 all interact with the cytoplasmic domain
(Wang et al., 1998). In addition, crosslinking 4-1BB
of 4-1BB and mutation analysis showed the involve-
with agonistic monoclonal antibody enhanced HIV-1
ment of the runs of acidic residues in the cytoplasmic
replication.Administrationofmonoclonalantibodies
domainof4-1BB(Jangetal.,1998).Jangetal.(1998)
to the 4-1BB molecule can completely eradicate
and Arch and Thompson (1998) demonstrated that
establishedtumors (Meleroet al.,1997).Shufordand
4-1BB crosslinking induces activation of NF(cid:20)B and
colleagues (1997) demonstrated that in vivo adminis-
is known to be inhibited by dominant negative
tration of such monoclonal antibodies enhances
TRAF2andNF(cid:20)B-inducingkinase(NIK).Ourlabo-
graft-versus-host disease (GVHD), and increases the
ratory also identified a putative binding site for the
rapidityofcardiacallograftandskintransplantrejec-
T cell-specific protein tyrosine kinase p56lck, in the
tion. The role played by 4-1BB in Hodgkin’s disease
cytoplasmic domain (Kim et al., 1993). The latter
(HD) suggests that eosinophils bearing ligands for
observation suggests that 4-1BB may be linked to the
4-1BB may act as an important element in the
src tyrosine kinase family signaling pathway, but this
pathology of HD (Gruss et al., 1996).
has not been investigated further as yet. A recent
study showed a role for apoptosis signal regulatory
kinase (ASK-1) and c-Jun N-terminal kinase (JNK)/
Phenotypes of receptor knockouts
stress-activating protein kinase (SAPK) in 4-1BB-
mediated T cell activation (Cannons et al., 1999). and receptor overexpression mice
Our laboratory has recently generated mice deficient
BIOLOGICAL CONSEQUENCES
in the 4-1BB molecule. Unpublished data from our
OF ACTIVATING OR INHIBITING laboratory point out that the absence of 4-1BB leads
to dysregulated lymphocyte activation and abnor-
RECEPTOR AND
malities in the myeloid progenitor pool. These mice,
PATHOPHYSIOLOGY
under nonimmunized conditions, tend to secrete
increased amounts of IgG2a, IgA; increased anti-
Following introduction of agonistic antibodies to 4- gen-specific(T-dependent)IgG1,IgG2a,andofferno
1BB to activate quiescent T cells it is generally 4–5 interference in the IgG class-switch.
days before a response is noted (Kim et al., 1998),
possibly because T cells require 2–3 daysto bring out
optimalcellsurfaceexpressionof4-1BB(Polloketal.,
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ACKNOWLEDGEMENTS
detectableinseraofpatientswithrheumatoidarthritis.Eur.J.
Immunol.28,290–295.
Pollok,K.E.,Kim,Y.-J.,Zhou,Z.,Hurtado,J.C.,Kim,K.-K.,
SRC funds to IRC from the Korean Ministry of
Pickard, R. T., and Kwon, B. S. (1993). The inducible T cell
Science and Technology and NIH Grants (AI28125
antigen4-1BB:analysisofexpressionandfunction.J.Immunol.
150,771–781. and DE12156) are greatly appreciated.