Department of Immunology, Duke University Medical Center, Durham, North Carolina
Correspondence: You-Wen He, M.D., Ph.D., Department of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710. E-mail: he000004{at}mc.duke.edu
 TOP ABSTRACT INTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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has been shown to
promote thymocyte survival by activating the expression of
antiapoptotic protein Bcl-xL. ROR is also required for
the development of lymph nodes and Peyer’s patches. The orphan
receptors Nur77 and Nor1 are involved in TCR-mediated cell death and
thymocyte-negative selection. These studies provide novel insights into
the molecular mechanisms of T lymphocyte development.
Key Words: thymocyte apoptosis • thymocyte differentiation • TCR-
rearrangement • ROR • Nur-77 • negative selection
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TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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An important event of thymocyte maturation at the DP stage is TCR
gene rearrangement. TCR genes undergo primary and secondary
rearrangement. Primary rearrangement initiates from Js at the 5' end
of the locus [4
5
6
]. More 3' Js are used through
V-to-J secondary rearrangement that replaces the primary VJ
[7
, 8
]. If the primary rearrangement fails,
secondary rearrangements can test additional Vs located 5' and
additional Js located 3' to the primary VJ [8
,
9
]. Secondary rearrangement plays an important role in
the formation of a normal TCR repertoire, as DP thymocytes with limited
ability to undergo secondary rearrangement as a result of defective
recombination-activating gene expression have an unusually 5' biased
J repertoire [10
].
TCR gene rearrangement is regulated by two cis-acting
elements, the T early (TEA) promoter and the TCR enhancer (E)
[11
, 12
]. Mice lacking E have a profound
defect in TCR recombination and expression [12
],
whereas mice lacking TEA and its promoter exhibit defective
recombination involving the nine most 5' Js [11
].
Based on the defective 5' J use in TEA-/- mice, it is
proposed that the function of the TEA promoter is to act as a
"rearrangement focusing" element to force the initiation of TCR-
rearrangements to the 5' end of the J locus [11
].
Recent works demonstrate a role of the orphan receptor ROR/RORt
in regulating TCR repertoire formation [13
].
After successful rearrangement of TCR genes,
CD4+CD8+ DP thymocytes face a strict selection
process [14
]. DP thymocytes expressing a TCR with
intermediate affinity for self-peptide-major histocompatibility complex
(MHC) are positively selected and complete maturation. This process is
referred to as thymocyte positive selection. DP thymocytes expressing
TCR with too high affinity for self-peptide-MHC complex are deleted via
programmed cell death in a process termed negative selection. Negative
selection accounts for only a small fraction of cell death in the
thymus. A vast majority of DP thymocytes expressing TCR with too low
affinity to interact with self-peptide-MHC complex also undergo
programmed cell death, referred to as "death by neglect." The
molecular mechanisms underlying thymocyte positive and negative
selection are not well understood. TCR ligation by self-peptide-MHC
complex could result in positive or negative selection depending on the
types of stromal cells or bone marrow-derived cells. It is generally
believed that the avidity of thymocyte-stromal cell or thymocyte-bone
marrow-derived cell interaction will determine the fate of immature
thymocytes [14
, 15
]. Strong interaction
leads to negative selection while weak interaction results in positive
selection.
Negative selection of thymocytes appears to share some of the pathways that are used by T cell activation. For example, costimulatory molecules CD5, CD28, and CD43 may act together with TCR/CD3 complex to activate a pathway leading to programmed cell death of thymocytes [16 17 18 ]. In addition, the extracellular regulated kinase and mitogen-activated protein kinase pathways are involved in negative selection [19 , 20 ]. How thymocytes die in negative selection remains unclear. Antigen-induced thymocyte death, which mimics the process of negative selection, can be mediated through Fas-dependent and Fas-independent pathways [21 , 22 ]. Cortical thymocytes die primarily through Fas-independent pathway, whereas semi-mature CD4+CD8-CD24high thymocytes in medulla are deleted in a Fas-dependent manner [21 ]. Other death receptors such as tumor necrosis factor (TNF) receptor and DR3 have also been implicated in thymocyte negative selection [21 , 23 ]. However, it is not clear whether these death receptors trigger a caspase cascade in thymocytes undergoing negative selection as a result of conflicting reports [24 , 25 ]. Recent works show that the orphan receptors Nur77 and Nor-1 are involved in negative selection of thymocytes.
|
TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
|---|
(NR1F1), RORß (NR1F2), and ROR (NR1F3)
[26
, 27
]. The three ROR members share a
similar structure with a highly conserved DNA binding domain (DBD) at
the N-terminal portion and a less conserved putative ligand-binding
domain (LBD) at the C-terminal portion of the proteins. The DBD of RORs
is about 66 amino acids long, and most of the amino acids in this
region are identical in these three members. In contrast, the LBD of
RORs shares approximately 50% identity at the amino acid level
[27
]. The highly conserved DBD of RORs suggests that
these orphan receptors bind to the same DNA elements. Several in vitro
binding studies indeed showed that RORs bind to a consensus core
sequence of AGGTCA immediately preceded by a 6-bp A/T-rich region
[28
29
30
]. Members of the ROR subfamily bind to DNA as
monomers [27
]. Multiple isoforms have been identified
for each member of RORs. ROR is expressed in at least four different
isoforms, 1, 2, 3, and 4 in mouse [28
,
31
32
33
] and RORß in two different isoforms, ß1 and
ß2 [29
, 34
]. ROR also has two
different isoforms, ROR (1) and RORt (2)
[35
36
37
]. Interestingly, all the isoforms of each member
of RORs differ solely in the N-terminal domain outside of the DBD.
These isoforms have been generated by differential use of promoters or
alternative splicing of mRNA.
ROR is widely expressed. Among the various tissues expressing
ROR, higher expression levels were detected in the spleen, skeletal
muscle, testis, lens, retina, and the Purkinje cells of the cerebellum
[33
, 38
39
40
]. Genetic studies have
demonstrated that ROR plays a critical role in the development of
the central nervous system (CNS) and is disrupted in natural mutant
staggerer mice [41
42
43
]. Staggerer mice have
defects in the development of Purkinje cells and show significant
cerebellar abnormalities [44
45
46
]. It is interesting
that Staggerer mice also have a defect in thymocyte development
[47
]. The cerebellar defect of Staggerer mice has been
recapitulated in ROR-deficient mice generated by gene targeting
[41
, 42
]. However, it has not been
demonstrated whether ROR-deficient mice exhibit a similar defect of
thymocyte development observed in the staggerer mice. The defect of
thymocyte development in the staggerer mice might be caused by
mutations in a closely linked but independent genetic locus termed
small thymus (sty) [48
]. In addition to its role in the
development of CNS, ROR may act as a negative regulator of the
inflammatory response in vivo [49
]. When overexpressed
in smooth-muscle cells, ROR inhibits TNF--induced interleukin
(IL)-6, IL-8, and cyclooxygenase-2 expression. This inhibition is
likely through controlling the nuclear factor (NF)-
B signaling
pathway, as ROR binds to a ROR response element in the promoter for
IB, a NF-B inhibitor, and activates IB transcription,
which in turn, inhibits p65 nuclear translocation [49
].
It remains to be determined whether ROR plays a similar role in
regulating inflammatory cytokine production by lymphocytes. The
expression of RORß is relatively restricted. RORß is abundantly
expressed in areas of the CNS involving the processing of sensory
information, including spinal cord, thalamus, and sensory cerebellar
cortices [34
, 50
]. Multiple defects
including retinal degeneration and changed circadian activity have been
described in the RORß-deficient mice [51
]. Taken
together, these genetic studies have demonstrated important roles of
ROR and RORß in the development of the CNS. However, the roles of
these two members of the ROR family in the development and function of
the immune system have not been examined.
IN T LYMPHOCYTE DEVELOPMENT
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TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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(also named TOR for thymus orphan
receptor) was initially isolated through degeneracy reverse
transcriptase-polymerase chain reaction and low stringency
hybridization [35
, 36
]. ROR consists of
516 amino acids with an estimated molecular mass of 58 kD. When
cotransfected with thyroid hormone receptor and retinoic acid
receptor, ROR is able to repress the transcriptional
activities of these receptors on their corresponding response elements
[36
]. ROR is widely expressed in tissues including
the thymus, muscle, brain, heart, kidney, liver, and lung
[35
, 36
]. The second isoform of ROR,
RORt, was isolated in an expression-cloning experiment designed to
identify genes that are involved in TCR-mediated cell death
[37
]. RORt contains 495 amino acids and is
exclusively expressed in the thymus [37
]. It differs
from ROR in the first two exons. Recent data suggest that the
generation of ROR and RORt is controlled by different promoters
[52
]. Neither isoform is detected in the spleen and bone
marrow, indicating that B cells do not express this nuclear receptor
[37
].
ROR/RORt can protect T hybridoma cells from TCR-mediated cell
death when ectopically expressed. This protection is a result of an
inhibitory effect on Fas ligand (FasL) expression [37
].
ROR and RORt also inhibit IL-2 production by T cell hybridomas
without affecting early events of T cell activation such as
up-regulation of CD69 [37
]. The effect of this orphan
receptor on the expression of FasL and IL-2 is likely because of its
competition with NFAT for DNA binding [53
].
Nuclear factor of activated cells (NFAT) has been shown to bind to the
promoters of both genes. RORt was also found to negatively regulate
the transcription of c-Rel in vitro and in vivo [54
],
which is essential for IL-2 expression, as T lymphocytes from
c-Rel-deficient mice exhibit dramatically reduced capability to produce
IL-2 [55
, 56
]. These results suggest an in
vivo role of ROR/RORt in regulating cytokine production.
The expression of ROR and RORt in the thymus is tightly
regulated. Both isoforms are highly expressed in DP thymocytes,
gradually down-regulated as DP thymocytes are positively selected, and
completely turned off in mature SP thymocytes and peripheral T cells
[37
, 54
]. To test why the expression of
ROR/RORt is turned off in mature T cells, transgenic mice
ectopically expressing this orphan receptor in mature T cells were
generated. It was found that multiple functions of mature T cells in
RORt transgene (Tg) mice were affected [54
]. First,
the RORt Tg inhibited mature T lymphocytes from proliferation after
stimulation through the the TCR/CD3 complex. Second, similar to its
effect on T hybridoma cells, RORt inhibited IL-2 production by
mature T lymphocytes. The reduced proliferation of mature T cells in
RORt Tg mice was not secondary to the reduced production of IL-2, as
exogenous IL-2 did not restore the proliferation. Third, mature T cells
in RORt Tg mice also expressed lower levels of surface TCR
[54
]. These results are interesting in that RORt Tg
expression in mature T cells, even at low levels, conferred some
characteristics of immature DP thymocytes on these cells in terms of
their TCR expression level, proliferation, and IL-2 production in
response to TCR stimulation. The phenotypic similarity between the
mature T cells from RORt Tg mice and normal, immature DP cells
indicates that down-regulation of the expression of this orphan
receptor is essential for the maturation of DP thymocytes into SP
thymocytes. Furthermore, these results suggest that the expression
level of RORt in developing T cells could be used as a molecular
marker to measure their maturity.
Recent studies using ROR/RORt-deficient mice demonstrate critical
roles of this orphan receptor at multiple steps of thymocyte
development. The total thymocyte number in
ROR/RORt-/- mice was reduced to one-third of that
found in controls [57
, 58
]. DP thymocytes
were reduced by 60–80%, and CD4+ SP thymocytes were
reduced by 90% in the mutant mice. The diminished DP and SP thymocyte
populations in ROR/RORt-/- mice result from
increased cell death of DP cells and decreased differentiation of ISP
thymocytes to DP stage [13
, 57
,
58
]. The increased cell death of DP thymocytes in the
mutant mice is likely a result of a dramatically reduced expression of
antiapoptotic protein Bcl-xL [57
,
58
]. In supporting this, Tg expression of
Bcl-xL in ROR/RORt-/- mice restored
their thymic cellularity and corrected the massive cell death defect
[57
].
Thymocyte development in ROR/RORt-/- mice was also
impaired in the ISP-to-DP transition [13
]. The
impairment at this transition in ROR/RORt-/- mice
is reflected by a fivefold increased number of ISP thymocytes in thymi
of 3- to 4-week-old mice and a dramatic delay of thymocyte
development in young mutant mice. The molecular mechanisms regulating
the ISP-to-DP transition are poorly defined. Genetic studies have shown
that mice lacking two other transcription factors, T cell factor
(TCF-1) and HeLa E-box binding protein (HEB), exhibited a
similar defect in the ISP-to-DP transition [59
,
60
].
Is the impaired ISP-to-DP transition in ROR/RORt-/-
mice caused by a lack of Bcl-xL expression in DP cells? Two
lines of evidences suggest that this is unlikely. First, the impaired
ISP-to-DP transition is still observed in
ROR/RORt-/- x Bcl-xL Tg mice,
although the increased apoptosis of DP cells is corrected
[57
]. Moreover, Bcl-xL-/- mice
did not exhibit a similar defect in the transition from ISP to DP
[61
, 62
]. These results place
ROR/RORt, alongside TCF-1 and HEB, as important regulators of the
ISP to DP transition in thymocyte development.
Another in vivo role of ROR/RORt demonstrated in the mutant mice
is to regulate the cell-cycle status of DP thymocytes through
Bcl-xL expression. It was found that a large fraction of DP
thymocytes in ROR/RORt-/- mice displayed
unregulated entry into the S phase of the cell cycle
[57
]. Furthermore, the expression of the cyclin CDK2
inhibitor p27kip1 was dramatically reduced. The changes in
cell-cycle status of DP cells and expression of p27kip1 are
secondary to Bcl-xL expression, as Bcl-xL Tg
expression corrected the deregulated cell-cycle status of DP thymocytes
and the expression level of p27kip1 in
ROR/RORt-/- mice [57
].
RORt has been suggested to be a regulator of TCR- gene
recombination, as it binds to the TEA promoter in vitro
[52
]. Examination of the J repertoire in
ROR/RORt-/- mice revealed that 5' Js were
overrepresented, and 3' Js were underrepresented
[13
]. This is in sharp contrast to TEA-/-
mice, in which the use of 5' Js was impaired [11
] and
suggests that RORt is not required for the TEA promoter activity in
vivo. The impaired 3' J use in ROR/RORt-/- mice
is a result of defective V-to-J recombination and can be
corrected by the expression of Bcl-xL as a Tg
[13
]. Furthermore, Tg expression of Bcl-xL
not only corrected defective 3' J use in
ROR/RORt-/- thymocytes, but also skewed J use to
the extreme 3' end of the locus in ROR/RORt-/- and
wild-type mice [13
]. Bcl-xL Tg also induced
a skewed 3' J repertoire in positively selected T cells. These
results demonstrate that ROR/RORt regulates TCR rearrangement
and TCR- repertoire formation by controlling the survival window of
DP thymocytes. In addition, these data indicate that programmed cell
death of DP cells is not simply a consequence of failed positive
selection. Rather, it limits TCR secondary rearrangement and the
opportunities for positive selection and therefore represents an
important parameter that regulates the TCR- repertoire.
IN LYMPH NODE (LN) DEVELOPMENT
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TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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/RORt-/- mice
is that they lack LN and Peyer’s patches but retain a normal splenic
structure [57
]. LN development can be divided into
several distinct stages [63
]. Formation of lymphatic
sacs marks the beginning of LN organogenesis. This is followed by the
development of lymphatic vessels through endothelial sprouting from the
lymphatic sacs. In the next stage, invagination of mesenchymal
connective tissues into the lumen of growing lymph sacs creates LN
anlage. Migration of leukocyte into the LN anlage and the formation of
subcapsular sinus establish LN microstructure. To date, the following
molecules have also been shown to be involved in lymphoid
organogenesis: RANK, its ligand RANKL/TRANCE/OPGL, TRAF6, Id2, LT,
ß, and their receptors, IL-7R, IL-2Rc, chemokine receptor
BLR-1, RelA, and NIK [63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
]. These molecules regulate
the survival and/or differentiation of the hematopoietic or
nonhematopoietic cells in the establishment of secondary lymphoid
organs. The defects exhibited in mice lacking these molecules range
from lacking some of the LN to lacking all LN, with or without
disrupted spleen structure. For example, like
ROR/RORt-/- mice, Id2-/- mice also
lack most of the LN, including inguinal, iliac, sacral, mesenteric,
axillary, cervical LN, and Peyer’s patches but retain a normal spleen
structure [66
]. Mice deficient for lymphotoxin (LT)
or the LTß receptor lack all LN, whereas mice deficient for LTß or
OPGL/RANKL/TRANCE lack only some of LN. In contrast to RORt/ROR
and Id2-deficient mice, the splenic structure in most of the TNF
family member deficient mice is disrupted. The mechanism by which
RORt/ROR regulate LN development is not clear. The defective LN
development in these mice may be a result of the lack of the
CD45+CD4+CD3-IL-7R+4ß7+LTß+
hematopoietic cell population in fetal mesentery and intestines
[57
]. This population is found in the embryonic stage of
mouse development and has been proposed to play an instrumental role in
the establishment of lymphoid organ architecture [79
].
RORt/ROR may be required for the survival of the putative LN
precursors by activating Bcl-xL expression in these cells.
Alternatively, RORt/ROR may regulate expression of genes involved
in the migration of this population. Future experiments are required to
test these possibilities. |
TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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), Nurr1 (NGFI-Bß), and Nor1 (NGFI-B)
[1
, 2
]. The structural feature for the
members of this subfamily is that in addition to a central DBD and a
C-terminal LBD, a transactivation domain is localized at the N-terminal
portion. The DBD is >90% homology, and the LBD is intermediately
conserved in this subfamily. The transactivation domain is not well
conserved with a homology of 27% between Nur77 and Nurr1 or 21%
between Nur77 and Nor1 [80
]. Nur77 is widely expressed
in tissues including thymus, muscle, lung, liver, testis, ovary,
ventral prostate and the adrenal, thyroid, and pituitary glands
[81
82
83
84
85
]. Nurr1 is detected in thymus, osteoblasts,
liver, and pituitary gland [85
86
87
], and Nor1 is
expressed at a high level in the pituitary gland and at low levels in
thymus, kidney, heart, skeletal muscle, and adrenal glands
[87
88
89
]. Nur77 subfamily members have been shown to
bind DNA as monomers, homodimers, or heterodimers with RXR. Nur77 binds
to monomeric response elements containing AAAGGTCA. Nur77 was originally identified as an immediate early gene in response to NGF stimulation in PC12 pheochromocytoma cells [81 ]. The role of Nur77 in TCR-mediated apoptosis has been demonstrated in T cell hybridomas [90 , 91 ]. Nur77 was rapidly induced in T hybridoma cells undergoing TCR-mediated cell death. Expression of a dominant-negative Nur77 protein or antisense Nur77 mRNA blocked TCR-mediated apoptosis of these cells [90 , 91 ]. Furthermore, thymocytes undergoing TCR-mediated apoptosis also express high levels of Nur77, suggesting that Nur77 might play a role in thymocyte-negative selection. Transgenic mice expressing a dominant-negative form of Nur77 blocked antigen-induced apoptosis of DP thymocytes and prevented clonal deletion of self-reactive T cells [92 , 93 ]. In contrast, overexpression of full-length Nur77 in thymus resulted in massive apoptosis of thymocytes. The increased apoptosis of thymocytes in the full-length Nur77 transgenic mice could not be rescued by introducing a FasL mutation, indicating that the cell death is not a result of the increased expression of FasL. Therefore, FasL is not a major downstream target of Nur77 [92 , 94 ]. These results suggest that thymocyte negative selection depends on a pathway that requires Nur77 function. However, mice deficient for Nur77 showed no defect in thymocyte negative selection [95 ]. The normal thymic phenotype in Nur77-/- mice may be a result of a functional redundancy of Nor1 in the thymus. Nor1 is not only expressed in a similar pattern to Nur77, but also can induce massive apoptosis of thymocytes when overexpressed as a full-length protein [94 ]. A clear functional role of Nur77/Nor1 in thymocyte negative selection requires the generation of mice lacking Nur77 and Nor1. Besides its role in TCR-mediated lymphocyte death, Nur77 is also involved in T hybridoma death induced by thapsigargin [96 ], suggesting that Nur77 may regulate some shared death pathway in both types of apoptosis.
Recent advances showed that the regulation of Nur77 occurs at
transcription and protein levels. Myocyte enhancer factor-2 (MEF2), a
ubiquitously expressed transcription factor, is responsible for
calcium-dependent Nur77 transcription [97
,
98
]. In the absence of calcium, MEF2 is associated with a
protein complex containing transcriptional repressors Cabin 1 and mSin3
and histone deacetylases [98
]. In the presence of
calcium, activated calmodulin binds to Cabin 1 and releases it from
MEF2. Histone acetyltransferase P300 replaces Cabin 1 to form a
transactivating protein complex with MEF2, resulting in the
transcription of Nur77 [98
]. Upon its expression, Nur77
may recruit its own interacting partners for gene activation or
repression. AF2-dependent coactivator ASC-2 and corepressor SMRT have
been shown to interact with Nur77, directly or indirectly
[99
]. These interactions result in activation or
repression of reporter genes. The coactivation function of ASC-2 on
Nur77-mediated transcription depends on the presence of
Ca2+/calmodulin-dependent protein kinase IV (CaMKIV)
[99
]. Interestingly, CaMKIV also potentiates ROR- and
ROR-mediated transcription [100
], suggesting that
these orphan receptors use common kinases for their activities. Nur77
is also regulated at the protein level through phosphorylation of a
serine residue at position 350 by protein kinase Akt
[101
, 102
]. Phosphorylation of Ser-350 of
Nur77 by Akt dramatically decreases the transcriptional activity of
Nur77 and stimulates its association with 14-3-3, a protein family with
antiapoptotic function [103
]. These results suggest that
Akt antagonizes apoptosis by inhibiting the function of Nur77.
|
TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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Received January 23, 2002; revised April 7, 2002; accepted April 8, 2002.
|
TOPABSTRACTINTRODUCTIONT LYMPHOCYTE MATURATIONROR SUBFAMILYROR{gamma} IN T LYMPHOCYTE...ROR{gamma} IN LYMPH NODE...Nur77 SUBFAMILY IN THYMOCYTE...CONCLUDING REMARKSREFERENCES |
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