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B Is Required for the Positive Selection of CD8+ Thymocytes1
*
Laboratory of Cardiovascular Biology, Harvard School of Public Health, Boston, MA 02115; and
Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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B in T cell development, we analyzed
thymocyte ontogeny in transgenic (mutant I-B
(mI-B)) mice
that express a superinhibitory form of the NF-B inhibitory protein,
I-B (I-BA32/36), under the control of the T
cell-specific CD2 promoter and enhancer. Thymi from mI-B mice
contained increased numbers of double-positive (DP) and decreased
numbers of both CD4+ and CD8+ single-positive
cells, consistent with a block in DP thymocyte maturation. In addition,
expression of CD69, a marker of positive selection, was decreased on DP
thymocytes from the mI-B mice. To test directly whether NF-B
was required for positive or negative selection, we generated
mI-B mice expressing the H-Y or 2C ß TCR transgenes.
Expression of the I-BA32/36 transgene caused a block
in the positive selection of CD8+ single-positive cells in
both strains of TCR transgenic animals. In contrast, negative selection
was unaffected by expression of the I-BA32/36
transgene. Taken together, these results identified a NF-B-dependent
transcriptional pathway that is selectively required for the positive
selection of CD8+ thymocytes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß TCR nor the CD4 or CD8 coreceptor. Following
expression of a pre-TCR, these DN cells expand and differentiate into
double-positive (DP) thymocytes that coexpress both CD4 and CD8, as
well as the ß TCR. DP thymocytes undergo two important selection
steps en route to differentiating into mature
CD4+ or CD8+
single-positive (SP) mature T cells. DP cells that recognize
self-peptide + MHC molecules with high affinity are eliminated by
a process of apoptosis termed "negative selection," whereas DP
cells that recognize self-peptides + MHC with lower affinities are
rescued from apoptosis and stimulated to differentiate into SP
cells via a process called "positive selection." DP cells that fail
to recognize self-peptides + MHC die of "neglect" and therefore
fail to progress to the SP stage. Together, neglect and negative
selection result in the elimination of >95% of DP thymocytes and
ensure the development of a highly selected repertoire of mature SP T
cells that lack autoreactivity and can recognize a wide range of
foreign peptide Ags in the context of self-MHC molecules.
Recent studies have begun to elucidate the intracellular signaling
pathways underlying positive and negative selection (3).
Proteins involved in TCR-proximal signaling events, including Lck
(4), ZAP-70 (5), Cbl (6), Itk
(7, 8), p21ras (9), and
Vav (10, 11, 12) have been shown to alter positive and/or
negative selection when functionally inactivated in vivo. These
upstream signaling molecules initiate distal signaling cascades, which
ultimately activate transcription factors, including members of the
NF-AT, IFN-regulating factor, and NF-B families (13).
Recently, a differential function of mitogen-activated protein kinase
cascades in thymic selection has been elucidated. Positive selection
has been shown to require the extracellular signal-regulated kinase
pathway (14, 15, 16), whereas negative selection is regulated
by the c-Jun N-terminal kinase and the p38 mitogen-activated protein
kinase cascades (17, 18). Despite this recent progress, it
has remained unclear whether specific transcription factors
differentially regulate the positive and negative selection of immature
DP thymocytes.
Members of the NF-B family of transcription factors are important
regulators of development, inflammation, and immunity (reviewed in
Refs. 19, 20, 21). At least five NF-B genes are expressed
in mammals: NF-B1 (p50/p105), NF-B2 (p52/p100), c-Rel, RelA
(p65), and RelB. These NF-B proteins can bind to their cognate DNA
recognition sequence (GGGRNYYYCC) as homo- or heterodimers
(22). p50 homodimers lack transcriptional activating
potential and at least in some cases function as transcriptional
repressors. In contrast, heterodimers of p50 with c-rel, RelA, or RelB
activate transcription from NF-B-containing promoters and
enhancers.
The transcriptional activity of NF-B proteins is regulated by
dynamic alterations in their subcellular localization. Before
activation of the NF-B signaling pathway(s), preformed NF-B
proteins (with the exception of p50) are sequestered in the cytoplasm
by binding to one or more of three known inhibitory proteins (I-Bs).
Specific extracellular signals such as stimulation with TNF- or IL-1
lead to the activation of I-B kinases and the subsequent
phosphorylation of I-B (23). Phosphorylated I-B
undergoes proteosome-mediated degradation, resulting in the release of
bound NF-B subunits, which can then translocate to the nucleus to
activate NF-B-dependent transcription.
Previous studies have suggested that NF-B proteins might function as
important regulators of thymocyte development. c-Rel, p50, and RelA are
all expressed in both DP and SP thymocytes and TCR cross-linking
results in the nuclear translocation and activation of NF-B in these
cells (24, 25, 26). Furthermore, inhibition of NF-B
activation has been reported to block the differentiation of a DP
thymocyte cell line into SP cells in vitro (27).
A definitive analysis of the role of NF-B in thymocyte ontogeny
would require the inhibition of all family members in developing T
cells. This has been difficult to accomplish using classical
gene-targeting approaches due to the large numbers of different NF-B
family members expressed in thymocytes. To circumvent this problem, we
and others have produced transgenic mice overexpressing a
constitutively active superinhibitory form of I-B
(I-BA32/36) in which the I-B kinase
phosphorylation sites (Ser32 and
Ser36) have been mutated to Ala (26, 28, 29, 30, 31). Nuclear translocation of RelA, RelB, and c-Rel in
response to both TCR engagement and treatment with TNF- is abolished
in thymocytes from these transgenic mice (26).
In the studies described in this report, we have used
I-BA32/36 transgenic mice (mutant I-B
(mI-B) mice) to analyze the role of NF-B transcription factors
in thymocyte development and selection. The results show that NF-B
is not required for the development of DN or DP thymocytes. However, it
is selectively required for the positive (but not negative) selection
of CD8+ thymocytes. Based on these findings, we
conclude that distinct transcriptional pathways regulate positive and
negative selection of CD8+ thymocytes and that an
NF-B-dependent pathway operates selectively to promote the positive
selection of these cells in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The construction of the I-BA32/36
transgene and the production of mI-B transgenic mice on a CD-1
background has been described previously (26). The
I-BA32/36 transgene construct was
reinjected into the male pronucleus of fertilized single-cell embryos
of C57BL/6 mice (Taconic Farms, Germantown, NY). Microinjected embryos
were transferred to pseudopregnant BL/6 foster mothers to produce
C57BL/6 mI-B transgenic mice. H-2b H-Y and
H-2b 2C TCR transgenic mice on C57BL/6
backgrounds were generously provided by Dr. P. G. Ashton-Rickardt
(Gwen Knapp Center, University of Chicago, Chicago, IL) and Dr. J.
A. Bluestone (Ben May Institute, University of Chicago), respectively,
and were bred to the C57BL/6 mI-B mice to produce
double-transgenic progeny. Mice expressing the H-Y TCR and/or
I-BA32/36 transgenes were genotyped by PCR
(Perkin-Elmer, Norwalk, CT). Primers used to amplify DNA sequences
specific for the CD2 transgene were 5'GGGGCAGCAGAAAACTCATTGTCC-3'
and 5'-CTCCAGAGTCTCTTAAGCAGATAG-3'. To detect H-Y transgenes,
primers 5'-CAGACCCTCCTTGATCCTGGCCCTCCAGT-3' and
5'-CAGTCCGTGGACCAGCCTGATGCTCATGT-3' were used as described by
Waterhouse et al. (32). DBA/2 (H-2d)
mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and
mated with 2C TCR/mI-B double-transgenic mice. Expression of the
2C TCR and/or H-2d proteins was detected by flow
cytometric analysis (see below).
Cell culture
Single-cell suspensions of thymocytes were cultured at 37°C,
5% CO2 in RPMI 1640 (Life Technologies,
Rockville, MD) containing 10% heat-inactivated FCS (Life
Technologies), 100 U/ml penicillin/streptomycin (Life Technologies), 2
mM glutamine (Life Technologies), 0.1 mM nonessential amino acids (Life
Technologies), and 5.5 x 102 µM 2-ME
(Life Technologies). Thymocyte proliferation assays were performed in
96-well plates (Becton Dickinson, Mountain View, CA) that had been
coated with anti-TCRß (H57–97) (PharMingen, San Diego, CA)
mAbs at a concentration of 10 µg/ml. Following stimulation for
48 h, cells (0.5 x 106/ml) were pulsed
for 18 h at 37°C with [3H]thymidine
(Amersham, Arlington Heights, IL) (1 µCi/ml). Cells were transferred
onto glass fiber filtermats, and [3H]thymidine
incorporation was measured using a beta scintillation counter (Packard
Instruments, Meriden, CT).
FACS analysis
Single-cell suspensions of lymphocytes (1 x
106 cells) were washed in PBS and incubated in
PBS + 5% FCS for 30 min on ice with the following conjugated mAbs:
PE-anti-CD4 (RM4-5), FITC-anti-CD8 (53-6.7), PE-anti-CD25
(PC61), Cy-Chrome-anti-CD4 (RM4-5), allophycocyanin-anti-CD8
(53-6.7), FITC-anti-CD69 (H1.2F3) (PharMingen), and the
anti-H-Y TCR clonotypic mAb T3.70 (kindly provided by Dr. P.
G. Ashton-Rickardt, University of Chicago). Following staining, the
cells were washed in PBS and analyzed on a FACScalibur (Becton
Dickinson). Each plot represents analysis of
>104 events using Cell Quest (Becton Dickinson)
software. For the identification of mice expressing 2C TCRs,
H-2b protein, and/or H-2b/d
protein, the following Abs were used: FITC--Ld
(30-5-7S), biotin-anti-H-2Kb (Y3),
FITC-anti-2C TCR (1B2) (kindly provided by Dr. Jeffrey A. Bluestone
(University of Chicago) (33)), and streptavidin-PE
(PharMingen).
Western blot analysis
Western blot analyses of thymocyte and splenocyte extracts were performed as described previously (26).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
transgenic mice
We have previously described the generation and characterization
of CD1 transgenic mice expressing a constitutively active
superinhibitory mutant form of the I-B protein
(I-BA32/36) under the control of the T
cell-specific CD2 promoter/enhancer (26). Thymocytes and T
cells from these transgenic mice displayed a complete block in NF-B
activation following either TCR cross-linking or treatment with
TNF-. The same transgenic construct was reinjected into the
pronuclei of single-cell fertilized C57BL/6 embryos to obtain
I-BA32/36 transgenic mice on a C57BL/6
background (hereafter referred to as mI-B mice).
The expression and function of the
I-BA32/36 transgene in the C57BL/6 and CD-1
backgrounds was compared by immunoblotting and thymocyte proliferation
assays. As shown in Fig. 1
A,
the level of expression of I-BA32/36 in
transgenic thymocytes was comparable in both mouse strains and
approximated the level of expression of endogenous I-B in
wild-type CD1 and C57BL/6 thymocytes. Expression of the
I-BA32/36 transgene resulted in a complete
block of NF-B activation and nuclear translocation in thymocytes
from these mice (Ref. 26 and data not shown). This
inhibition of NF-B activation was associated with a dramatic
reduction of thymocyte proliferation in response to TCR cross-linking
(Fig. 1B). As reported previously, the inhibition of
thymocyte proliferation was partially rescued by the addition of
exogenous IL-2 (29).
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B in T cell development,
we analyzed thymocyte cellularity and subsets from wild-type and
mI-B mice by flow cytometry (Fig. 2). As shown in Fig. 2A, all
thymocyte subsets were present in the mI-B mice. Thus, NF-B is
not required for thymocyte differentiation. However, the total number
of thymocytes was increased 1.9-fold in the mI-B mice as compared
with control C57BL/6 mice (p = 0.003) (Fig. 2B). This increase in total thymocyte numbers was due to a
significant increase in the numbers (and percentages) of DP thymocytes
and a concomitant decrease in the proportions of both
CD4+ and CD8+ SP
thymocytes. The same phenotype was observed in three independently
derived lines of transgenic mice: two lines of CD1 mice expressing the
I-BA32/36 transgene under the control of
the CD2 promoter/enhancer or the proximal lck
promoter (data not shown) and one line of C57BL/6 mice expressing the
same transgene under the control of the CD2
promoter/enhancer (Fig. 2). However, it should be noted that this
phenotype, although present, was subtle in the line of CD1 mI-B
transgenic mice that we have described previously (26).
Taken together, these results demonstrated that inactivation of
NF-B-dependent transcription resulted in an accumulation of
thymocytes at the DP stage of T cell differentiation.
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B transgenic mice
might have reflected defects in either positive or negative selection
(or both). To begin to address this question, we analyzed DP thymocytes
from the mI-B mice for expression of CD69 by flow cytometry (Fig. 3). Cell surface expression of CD69 is
normally induced in DP cells undergoing positive selection (35, 36). The percentage of CD69+ DP thymocytes
in the mI-B mice was reduced by 
50% as compared with
wild-type C57BL/6 littermates. This finding suggested a defect in
positive selection in the transgenic mice. In addition, four-color flow
cytometric analysis of DP thymocytes revealed that, unlike wild-type
thymocytes, a significant proportion of mI-B thymocytes expressed
high levels of the high affinity IL-2 receptor, CD25. These
CD25+ DP thymocytes expressed normal levels of
CD44 and CD3 (data not shown) but lacked CD69 expression. The
significance of this finding remains unclear. However, it may reflect a
defect in the normal down-regulation of CD25 expression that usually
occurs as DN cells differentiate into DP thymocytes.
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B is required for positive selection of DP thymocytes
To better define the role of NF-B in positive and negative
selection, we crossed the mI-B mice to ß TCR transgenic mice
specific for either the H-Y or 2C Ag. The H-Y TCR is specific for the
male (H-Y) Ag presented by H-2Db MHC class I
molecules. H-Y TCR transgenic CD8+ SP cells are
positively selected in female H-Y TCR, H-2b mice
and negatively selected in male H-2Db mice
(37, 38). The CD4/CD8 profiles of thymocytes from female
H-Y TCR transgenic mice (H-Y) or double-transgenic (H-Y/mI-B)
mice are shown in Fig. 4. Female
double-transgenic mI-B, H-Y TCR mice displayed a significant
increase in DP thymocytes (85% DP in the H-Y/mI-B mice as
compared with 54% in the female H-Y mice) and a concomitant sixfold
decrease in CD8+ SP thymocytes as compared with
female H-Y TCR single-transgenic littermates. Staining of thymocytes
with a clonotypic mAb directed against the transgenic H-Y TCR (T3.70)
confirmed that the maturation of CD8+ H-Y
TCR+ thymocytes was severely inhibited in the
mI-B, H-Y TCR double-transgenic mice (Fig. 4). Thus, positive
selection of the TCR transgenic DP thymocytes was dramatically
inhibited by inhibition of the NF-B signaling pathway in DP
thymocytes.
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B in positive selection was
generalizable or instead was specific for the H-Y TCR transgenic mice,
we crossed the mI-B mice to mice transgenic for the 2C TCR.
CD8+ 2C TCR transgenic T cells are positively
selected on an H-2b background (39).
However, unlike wild-type or H-Y transgenic mice, 2C TCR transgenic
animals typically lack
CD4brightCD8bright DP
thymocytes because DP 2C TCR thymocytes are strongly positively
selected in H-2b mice (40, 41) (Fig. 5). In contrast,
CD4brightCD8bright DP
thymocytes were easily identified in 2c/mI-B, double-transgenic
mice (Fig. 5). Although the proportion of these DP thymocytes did not
reach wild-type levels, their presence suggested that inhibition of
NF-B activity blocked positive selection of 2C TCR thymocytes. In
support of this model, the development of mature
CD8+ SP T cells was markedly impaired in the
mI-B, 2C TCR double-transgenic mice as compared with 2C TCR
single-transgenic littermates (Fig. 5). Thus, inhibition of the NF-B
signaling pathway inhibited positive selection of DP thymocytes both in
wild-type mice and in two different strains of TCR transgenic animals.
From these results we conclude that a NF-B-mediated signal is
required for positive selection.
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B is not required for the negative selection of DP thymocytes
We used the mI-B, H-Y TCR and mI-B, 2C TCR
double-transgenic mice to determine whether NF-B signaling was also
required for negative selection. As reported previously and shown in
Fig. 6, DP thymocytes from H-Y TCR
transgenic mice are negatively selected in male
H-2Db mice. Negative selection in these male mice
is characterized by markedly reduced thymocyte numbers and the absence
of DP and SP thymocytes (37, 42). As shown in Fig. 6, expression of the mI-B transgene did not rescue H-Y TCR
transgenic DP cells from negative selection in the male mice. Thymocyte
numbers and profiles were equivalent in the H-Y TCR and H-Y TCR,
mI-B mice. Similarly, expression of mI-B did not alter the
negative selection of 2C TCR transgenic DP thymocytes, which is
observed on a class I MHC Ld background (Fig. 7). 2C TCR x DBA and 2C
TCR/mI-B x DBA mice had similar thymocyte numbers (2.5
x 106 vs 3.0 x 106)
and similar thymocyte profiles (Fig. 7). The levels of expression of
the clonotypic 2C TCR were identical on 2C TCR x DBA and 2C
TCR/mI-B x DBA thymocytes as assessed by flow cytometry
(data not shown). Taken together, these results demonstrated that
NF-B signaling is not required for the negative selection of
CD8+ thymocytes.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B
proteins in regulating mature T cell proliferation and function, the
role of this family of transcription factors in regulating T cell
development in vivo remained largely undefined. In the studies
described in this report, we have used mI-B transgenic mice that
lack NF-B activity in the thymus in conjunction with TCR transgenic
mice to analyze the role of NF-B in the positive and negative
selection of DP thymocytes. The results demonstrated that NF-B
proteins are required for positive selection of
CD8+ cells in both wild-type and TCR transgenic
mice but are not necessary for negative selection in vivo. These
findings have important implications for our understanding of the
molecular mechanisms that shape the T cell repertoire during thymocyte
development.
Our finding of an essential role for NF-B proteins in positive
selection is consistent with previous studies that have observed the
specific accumulation of NF-B proteins in the nuclei of
CD69+ DP thymocytes undergoing positive selection
(43). They are also in agreement with a recent report
showing decreased positive selection in transgenic mice overexpressing
wild-type (as opposed to constitutively active mutant) I-B
(31) and with a report demonstrating decreased numbers of
CD8+ TCRhigh thymocytes in
transgenic mice expressing a distinct, constitutively active mutant
form of I-B (29). They are also in accord with
studies in which the differentiation of a DP thymoma cell line into a
SP cell in vitro was shown to be dependent on the activation of NF-B
(27). In contrast, our results differ from those of
Ferreira et al. (28) who reported normal thymic
cellularity and CD4/CD8 ratios in transgenic mice expressing the
mI-B transgene under the control of the proximal lck
promoter. This difference may reflect the different temporal or
quantitative levels of transgene expression produced with the two
different promoters. Alternatively, the effects of mI-B
expression on positive selection may not have been detected by Ferreira
et al. (28), who did not investigate the role of the
mI-B transgene on positive selection in TCR transgenic
backgrounds.
A number of different mechanisms might explain the observed requirement
for NF-B in positive selection. First, in some cell types, NF-B
signaling is required to rescue cells from apoptosis produced by
cytokines such as TNF- or IL-1. Thus, it is possible that activation
of the NF-B pathway in DP thymocytes during positive selection
similarly rescues DP thymocytes from a default pathway of
neglect-associated apoptosis. This model would be consistent with our
finding of increased thymic cellularity and increased numbers of DP
thymocytes in the mI-B mice, which have not been observed in
other mouse models with defective positive selection (14).
In fact, we have reported previously that mI-B DP thymocytes are
resistant to apoptosis induced by in vivo administration of
anti-CD3 mAb (26). To determine whether this
represents a general resistance of these cells to multiple apoptotic
stimuli, we have compared the susceptibility of wild-type and
mI-B DP thymocytes with cell death induced by TNF-,
dexamethasone, and 
-irradiation (Ref. 26 and data not
shown). In all cases tested, the mI-B transgenic DP thymocytes
displayed equivalent or decreased susceptibility to apoptosis as
compared with their wild-type counterparts. Thus, we currently have no
evidence for a generalized cell autonomous role for NF-B in
enhancing the resistance of DP thymocytes to apoptosis. However, it
remains possible that unique death signals contribute to the apoptosis
of DP thymocytes undergoing death from neglect and that NF-B is
capable of specifically inhibiting these pathways in response to a
TCR-mediated positive selection signal.
It is also possible that NF-B might regulate the expression of genes
required for the maturation (differentiation) of DP thymocytes before
or during positive selection (31). Such gene products
might regulate positive selective signaling directly or alternatively
might be required for the appropriate development of DP cells that are
competent to receive these signals. To begin to address this
possibility, we have studied the expression of signal transduction
molecules that are known to be involved in positive selection in the
mI-B thymocytes. Expression of ZAP-70 (5), Cbl
(44), and p56lck (45)
appear to be normal in DP thymocytes from the mI-B transgenic
mice (data not shown). Despite these initial results, the availability
of DP cells from the mI-B mice in conjunction with subtraction
hybridization and cDNA array technologies should allow the
identification of potential downstream targets of NF-B that are
important regulators of positive selection in vivo.
The proximal signal transduction pathways that activate NF-B during
the positive selection of DP thymocytes also remain largely unknown. A
recent study demonstrated that the 
isoform of PKC specifically
activates NF-B in peripheral SP T cells in response to TCR signaling
(46). Interestingly, however, this pathway was not
operative in thymocytes. Thus, it appears likely that there are novel
and distinct signal transduction pathways that regulate NF-B
activity in thymocytes in response to TCR engagement. In this regard it
will be of interest to determine whether unique isoforms of PKC are
expressed in DP thymocytes and, if so, whether these PKC isoforms are
required for positive selection.
In summary, our results demonstrate that distinct transcriptional
pathways regulate the positive and negative selection of DP thymocytes
in vivo and that NF-B signaling is selectively required for positive
selection. The availability of the mI-B mice should allow a
molecular dissection of the signal transduction pathway(s) that
regulates positive selection and as such will significantly enhance our
understanding of T cell development and lay the foundation for
approaches designed to therapeutically manipulate T cell immunity.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jeffrey M. Leiden, Harvard School of Public Health, Building II, Room 117, 677 Huntington Avenue, Boston, MA 02115.
3 Abbreviations used in this paper: DN, double-negative; DP, double-positive; SP, single-positive; I-B, inhibitory protein that dissociates from NF-B; mI-B, mutant I-B.
Received for publication April 17, 2000. Accepted for publication August 9, 2000.
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 L. Espinosa, S. Santos, J. Ingles-Esteve, P. Munoz-Canoves, and A. Bigas p65-NF{kappa}B synergizes with Notch to activate transcription by triggering cytoplasmic translocation of the nuclear receptor corepressor N-CoR J. Cell Sci., March 15, 2002; 115(6): 1295 - 1303. [Abstract] [Full Text] [PDF]
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M. S. Robles, E. Leonardo, L. M. Criado, M. Izquierdo, and C. Martinez-A. Inhibitor of Apoptosis Protein from Orgyia pseudotsugata Nuclear Polyhedrosis Virus Provides a Costimulatory Signal Required for Optimal Proliferation of Developing Thymocytes J. Immunol., February 15, 2002; 168(4): 1770 - 1779. [Abstract] [Full Text] [PDF]
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A. L. Mora, S. Stanley, W. Armistead, A. C. Chan, and M. Boothby Inefficient ZAP-70 Phosphorylation and Decreased Thymic Selection In Vivo Result from Inhibition of NF-{kappa}B/Rel J. Immunol., November 15, 2001; 167(10): 5628 - 5635. [Abstract] [Full Text] [PDF]
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) or with anti-TCR
Abs (10 µg/ml) plus IL-2 (50 U/ml) (
). Proliferation was measured
by [3H]thymidine incorporation.
