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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-06-1855.
IMMUNOBIOLOGY
From the Institute of Biochemistry and Ludwig
Institute for Cancer Research, Lausanne Branch, University of Lausanne,
Epalinges, Switzerland; Department of Genetics and
Microbiology, University of Geneva, Medical School, Geneva,
Switzerland; Pediatric Immunology, Departments of Research
and Clinical-biological Sciences, and the Children's Hospital,
University of Basel, Switzerland; Department for
Immunology, University Clinics Ulm, Germany.
Major histocompatibility complex class II (MHCII)
expression is regulated by the transcriptional coactivator CIITA.
Positive selection of CD4+ T cells is abrogated in mice
lacking one of the promoters (pIV) of the Mhc2ta gene. This
is entirely due to the absence of MHCII expression in thymic epithelia,
as demonstrated by bone marrow transfer experiments between wild-type
and pIV Major histocompatibility complex class II
(MHCII) molecules are crucial for the development, survival, and
activation of CD4+ T cells. Recognition of
self-peptide-MHCII complexes on cortical thymic epithelial cells
(cTECs) determines whether or not immature CD4+ thymocytes
are positively selected.1 Negative selection, mediated by
MHCII+ thymic dendritic cells (DCs),2 results
in the deletion of autoreactive CD4+ T cells. In the
periphery, peptide-MHCII complexes expressed on antigen-presenting
cells (APCs) induce the activation, proliferation, and differentiation
of CD4+ T helper cells. The central importance of these
functions is illustrated by the phenotype of MHCII-deficient mouse
strains,3-5 by the clinical course of patients suffering
from bare lymphocyte syndrome (BLS),6-10 and by CIITA and
RFX5-deficient mice, 2 murine models of BLS.11-14 Patients
with BLS suffer from a severe primary immunodeficiency that is entirely
attributable to the nearly complete absence of MHCII
expression.6-10 Patients with BLS, as well as mice
deficient for MHCII, CIITA, and RFX5, exhibit impaired maturation of
CD4+ T cells and are unable to mount efficient
CD4+ T helper cell-dependent immune responses.
CIITA is one of the 4 genes affected in BLS.6,7 It now is
widely recognized to be the master regulator of MHCII expression. In
most instances, it is the expression of CIITA that dictates the tightly
controlled pattern of MHCII expression. Only MHCII+ APCs (B
cells, DCs, macrophages) express CIITA constitutively. The expression
of CIITA, and thus of MHCII genes, can be activated in
MHCII We have recently generated mice carrying a targeted deletion of
promoter IV (pIV) (Figure 1).
pIV
Surprisingly, pIV In this study we characterized the residual population of
CD4+ T cells in pIV Mice and generation of bone marrow chimeras
Cytofluorimetric analysis
Immunohistochemistry Sections (8-µm) from frozen adult organs and whole newborn mice were air dried, fixed in ice-cold acetone, blocked in phosphate-buffered saline (PBS) containing 0.6% H2O2, 5% goat serum and 0.1% NaN3, and stained with digoxygenin-conjugated antibody directed against MHCII (M5/114), F4/80 (Serotec no. MCAP497), CD11c (HL3; Pharmingen), and keratin (antipankeratin serum provided by E. Reichmann, Zurich, Switzerland). Staining was revealed using antidigoxygenin peroxidase and 3-amino-9-ethyl carbazole (Sigma-Aldrich) to give a red precipitate. Sections were counterstained with methylene blue.Immunofluorescence For detection of MHCII expression by medullary epithelial cells, thymuses were isolated and embedded in cryoembedding media (Tissue-Tek; Sakura Finetek Europe BV, Zoeterwoude, The Netherlands). Frozen samples were cut into sections 6 mm thick, fixed with 4% paraformaldehyde/PBS, and exposed to PBS with 1% fetal calf serum 0.1% Tween at pH 7.3 for 10 minutes before incubation with primary antibody for 1 hour at room temperature. Washing was repeated before incubation with the secondary antibody (20 minutes at room temperature). Isotype controls were used in all experiments. Thymic sections were stained for MTS10 (Pharmingen) and costained against I-A (AF6-120.1;
Pharmingen).32 Medullary areas were microscopically localized and analyzed by 2-color immunofluorescence with a confocal microscope (Carl-Zeiss AG, Feldbach, Switzerland).
Positive selection of CD4+ T cells is abrogated in
pIV / mice.25 The single-positive
CD4+ T-cell numbers and percentages in pIV /
thymuses did not exceed those found in MHCII-deficient mice (Figure 2A). In contrast, CD8+ and
double-positive CD4+ CD8+ thymocytes are
present in normal or slightly increased numbers. In the peripheral
lymphoid organs, the percentage of CD4+ T cells is reduced
to 1%-5% of total lymphocyte numbers (Figure 2B-C), while that of
CD8+ T cells is markedly increased. The extent of the
CD4+ T-cell deficiency in pIV / mice was
surprising because MHCII expression is normal on B cells, macrophages,
and DCs in all organs, including the thymus.25 Since
peripheral MHC/peptide engagements have been shown to be necessary for
the survival and homeostatic expansion of CD4+ T
cells,26,27 the peripheral MHCII+ environment
of pIV / mice should permit the survival and
accumulation of any positively selected CD4+ T cells. In
spite of this, CD4+ T-cell counts are as low as in mice
that have a complete lack of MHCII expression, such as CIITA, RFX5, and
MHCII-deficient mutants.
There are 2 explanations that could account for the loss of
CD4+ T cells. First, pIV could be essential for MHCII
expression in the thymic compartment that drives positive selection of
CD4+ T cells. The lack of MCHII expression in
pIV When both the recipient and donor phenotypes are wild type, all
lymphocyte populations are reconstituted to normal levels (Table 1,
group A). This is also true when wild-type mice are reconstituted with
pIV pIV / mice is characterized by an
abnormal pattern of MHCII expression (Figure
3A). In wild-type thymuses, the cortex
shows a fine reticular pattern of MHCII expression that is
characteristic of the epithelial cell matrix. In the medulla, the
staining is more diffuse and is attributable to DCs, B cells, macrophages, and medullary epithelial cells. In pIV /
mice, the cortical reticular staining is absent, indicating that the
cortical thymic epithelial cells (cTECs) lack MHCII expression. Only
patchy areas of MHCII expression remain in the cortex. In contrast, the
diffuse staining of the medulla is similar to wild-type controls. By
staining of adjacent sections, the patchy MHCII expression in the
cortex was found to colocalize with F4/80 positive macrophages. CD11c-positive cells, on the other hand, were restricted to the medulla
and corticomedullary junction, in accordance with previous studies.34 Finally, the fine reticular stain obtained with
an antikeratin antibody is consistent with a conserved architecture of
the thymic stroma. Medullary thymic epithelial cells (mTECs) were
analyzed by immunofluorescence for MHCII expression (Figure 3B). In
control pIV+/ thymic medulla, the majority of MTS10+
cells (major mTECs) express MHCII. Strikingly, in pIV /
mice MTS10+ mTECs do not express MHCII. The absence of MHCII expression
by mTECs has been confirmed by FACS experiments (data not
shown).
Thymocytes acquire MHCII molecules by passive transfer from TECs Mouse T cells do not express significant amounts of CIITA and are consequently devoid of MHCII molecules. However, experiments with radiation chimeras35 have indicated that mouse thymocytes can acquire MHCII molecules in a cell contact-dependent fashion. Thymocytes acquire these MHCII molecules by passive transfer from an unidentified thymic stromal cell.36 Strikingly, the passive transfer of MHCII to CD4+CD8+ thymocytes is abrogated in pIV / mice (Figure 3C). In
irradiated recipients reconstituted with pIV / donor
cells, the passive MHCII transfer to thymocytes was corrected only if
the host thymus is wild type (Figure 3D and data not shown). In
contrast, wild-type thymocytes grafted into irradiated
pIV / hosts remain MHCII . The lack of
MHCII transfer in pIV / mice is complete, as shown by
the negative control (I-A![]() / mice) in Figure 3E. These
observations confirm that the presence of MHCII molecules at the
surface of thymocytes results from a passive transfer from cTECs
or mTECs.
Negative selection by endogenous mtv superantigens
is conserved in pIV / thymuses strongly argue that the
CD4+ T-cell deficiency in pIV / mice is
entirely attributable to the lack of MHCII expression by cortical
thymic epithelial cells (cTECs). In contrast to other MHCII-deficient
mutants, pIV / mice retain normal MHCII expression on B
cells, DCs, and macrophages in both the thymus and the
periphery.25 This provided a unique opportunity to test
whether MHCII+ APCs can perform negative selection in the
absence of positive selection of CD4+ T cells. With this
aim, we examined clonal deletion of T cells in pIV /
mice. T cells expressing V 5 and V 11 TCRs are deleted in the thymus of mouse strains that express I-E and retroviral superantigens encoded by mtv-8 and -9.37 Because
pIV / mice were generated in a mixed B6/129 background
(b haplotype), they lack a functional I-E gene. To obtain efficient,
superantigen-mediated deletion we therefore introduced a functional I-E
allele by crossing the pIV / mice with B10.BR mice.
Figure 4A compares the frequency of
CD4+ T cells expressing V 5, V 11, and V 8 in the
presence and absence of the I-E gene. In wild-type mice and in
pIV / mice, introduction of the I-E gene has no
effect on the control V 8 family. In wild-type mice, introduction of
the I-E gene leads to efficient deletion of the susceptible V 5
and V 11 families. A deletion of the V 11 family and, to a lesser
extent, of the V 5 subset was also observed in the residual
CD4+ T-cell population of pIV / mice. The
fact that deletion in the CD4+ V 5 subset is only partial
in pIV / mice may be explained by the recently described
MHCI- and MHCII-independent population of CD4+ T
cells.38 This population displays a 6-fold increase in
V 5 expression, which becomes apparent in the residual
CD4+ T-cell compartment of pIV / mice. In
the CD8+ T-cell compartment, the I-E dependent,
superantigen-mediated deletion of the V 5 and V 11 families was, as
expected, similar in pIV / and control littermates
(Figure 4B). There was again no change in the percentage of V 8+
CD4+ T cells after introduction of the I-E gene. Taken
together, these results establish that superantigen-mediated negative
selection of CD4+ T cells occurs normally in
pIV / mice. The residual CD4+ thymocytes in
pIV / mice are negatively selected despite the defect in
their positive selection. This defect in positive selection is as
strong in the B10BR background as it is in the mixed Sv129-C57Bl/6
background (compare Figure 4C to Figure 2).
Thymocytes and peripheral CD4+ T cells exhibit the same
activated phenotype in pIV / mice present the same anomalies as their
counterparts isolated from animals fully deficient in MHCII molecules.
CD4+ thymocytes have reduced TCR levels in both
I-A![]() / and pIV / mice. MHCII deficiency
also has been reported to have an impact upstream of the
CD4+ single-positive stage, leading to elevated CD4 and TCR
levels on double-positive CD4+CD8+
thymocytes.39 This phenotype is again reproduced in the
pIV / animals.
The similarity between pIV There are 2 explanations that could account for the unusual activated
phenotype of the residual CD4+ T cells in the
pIV
Taken together, our results show that the activated phenotype of
CD4+ T cells is a consequence of deficient MHCII expression
on cTECs and mTECs. This is consistent with the finding that the
residual CD4+ T cells in pIV A large proportion of the residual CD4+ T cells in
pIV / mice contain a higher
proportion of V 8+ and V 7+ cells (see Figure 7). These
features are typical of NKT cells.40,41 This led us to
suspect that the residual CD4+ T-cell population in
pIV / mice contains a high proportion of NKT cells. We
therefore performed a 4-color FACS analysis with antibodies directed
against CD4, TCR- , and NK1.1, and with CD1 tetramers coupled to
GalCer (Figure 7A). The tetramers
allowed us to detect NKT cells that stain negative for the NK1.1
marker.42 CD4+ T cells from
pIV / , MHCII-deficient, and wild-type mice were found to
comprise similar absolute numbers of NK1.1+ and CD1-restricted cells.
In contrast, the NK1.1-CD1 GalCer CD4+ T cells, which
comprise the classical MHCII-restricted CD4+ T cells, are
much less abundant in the MHCII-deficient and pIV /
animals. The consequence is a considerably higher proportion of NKT
cells in the pIV / and MHCII-deficient animals (up to
half of the total number of CD4+ T cells).
Since NKT cells display a strong V To complete our characterization of the T-cell population in
pIV No requirement for IL-7R signaling in MHCII expression by cTECs The Jak/signal transducers and activators of transription (STAT) pathway is able to activate Mhc2ta transcription through promoter IV. We addressed the question whether the STAT-1,-3,-5 associated cytokine receptors for IL-7 or IL-15 could be implicated in promoter IV activation. It has been previously shown that IL-7 plays an important role in expansion of positively selected T cells.43,44 It has not, however, been shown whether IL-7 or other common gamma chain cytokines are required for MHCII expression in cTECs and hence positive selection of CD4+ T cells. For this purpose, we produced bone marrow chimeras between IL-7R-deficient recipients28 and wild-type bone marrow. In these chimeras, IL-7 production and signaling in thymocytes is normal, but IL-7 cannot induce a signal in cTECs. As shown in Figure 8A, such mice show completely normal T-cell development in terms of numbers and CD4/CD8 proportions. Peripheral CD4 and CD8 T cells also are produced in normal numbers and relative frequencies in the spleen (Figure 8B). To address the question of the role of other common gamma chain-associated signals in MHCII expression by cTECs, we analyzed nude mice transplanted with common chain, c-kit KO thymuses under the kidney
capsule.30 Both type of thymuses developed normally and
induced normal selection of CD4+ T cells (Figure 8C). These
results rule out an absolute requirement of IL-7R or any of the common
gamma chain-associated cytokine signals in cTECs for MHCII expression
(see "Discussion").
Expression of pIV in cTECs is controlled by an unknown
IFN / mice are consistent with
previous studies showing that positive selection of CD4+ T
cells is driven mainly by MHCII+ cTECs. For instance,
positive selection of CD4+ T cells can be restored in an
otherwise MHCII negative host if the MHCII molecules are present
exclusively on cortical thymic epithelium.45-47 Bone
marrow-derived, MHCII+ APCs are largely unable to promote
CD4+ T-cell selection. Targeted expression of MHCII in DCs
fails to promote positive selection of CD4+ T
cells.34 MHCII-deficient mice reconstituted with wild-type bone marrow also demonstrated that MHCII+ APCs are unable
to promote positive selection of CD4+ T
cells.48
While MHCII expression is constitutive on cTECs in vivo, this
expression is lost when the cells are removed from the thymus and
maintained in 2-dimensional cultures in vitro.49 This
implies that there is a signal in the thymic microenvironment that
maintains MHCII expression turned on in cTECs. The nature of this
signal remains unknown. The pathway mediating IFN At the promoter level, 2 transcription factors (STAT1 and IRF1) have
been shown to be involved in IFN pIV of the Mhc2ta gene drives MHCII expression on mTECs pIV was demonstrated to be necessary for CIITA and MHCII expression in radio-resistant, nonhematopoietic cells.25 In this study, we further demonstrate that mTECs, radio-resistant cell types of epithelial origin,75 also strictly depend on pIV for MHCII expression. The promiscuous expression of peripheral tissue antigens by mTECs has been shown to promote T-cell negative selection or anergy (reviewed in Kyewski et al76). Transcription of genes encoding peripheral antigens is reduced in mTECs of Aire-deficient mice, altering central tolerance and causing autoimmunity.77 Since MHCII expression by mTECs is required for tolerance induction to several autoantigens,77 it could be anticipated that pIV / mice would also develop autoimmune disease.
Positive selection would first need to be restored in
pIV / mice, for instance, by re-expressing CIITA under
the control of a cTEC-specific promoter.47 Such an
experiment would help to address the consequences of the lack of MHCII
expression by mTECs in the presence of conserved negative selection by
bone marrow-derived APCs.
The residual CD4+ T-cell population in
pIV / mice, the phenotype of the residual
CD4+ T cells closely matches that of their counterparts in
the A![]() / mouse. They are characterized by lower
levels of TCR and an activated phenotype (CD44+
CD54+ CD62Llo). These characteristics do not
result from the lack of pIV in T cells, as pIV / bone
marrow-derived progenitors give rise to normal CD4+ T
cells when they are selected in a normal thymus.
In MHCII-deficient mice, NK1.1+ CD4+ T cells account for
40%-45% of the residual CD4+ T cells.78 A
4-color stain ( The 4-color staining also allows identification of the New implications concerning the key role of CIITA pIV The demonstration that pIV of the CIITA gene plays a crucial role in the generation of CD4+ T cells in the mouse has a number of potential implications for human diseases. First, patients with BLS including those having a deficiency in CIITA have low
CD4+ T-cell counts. This indicates that human cTECs
also depend on CIITA to express MHCII and drive positive selection of
CD4+ T cells. Second, the 3 CIITA promoters do not show any
polymorphism,79 suggesting that there may be a strong
selective advantage in maintaining these promoters invariant. For
instance, allelic variations of pIV in humans could have pathologic
repercussions on positive selection of CD4+ T cells. Given
the phenotype of the pIV / mouse, it will be interesting
to explore whether allelic variants of pIV or more severe mutations of
the Mhc2ta regulatory region could lead to CD4+
T-cell lymphopenia in humans. Patients diagnosed with a variety of
hereditary immunodeficiency syndromes have been reported to have a
reduction in the CD4/CD8 ratio. Common variable immunodeficiency is a
heterogeneous condition of unknown etiology for which not all
responsible genes have been identified (reviewed in Spickett et
al80). It is characterized by reduced serum IgG and, in
30% of the cases, by a reduced CD4/CD8 ratio. Recently, 2 cases of hereditary CD4+ T-cell lymphopenia with normal serum levels
were also reported.81 Interestingly both patients
presented with extensive warts. Epidermodysplasia verruciformis (EV) is
a heritable syndrome that is also characterized by extensive warts and
is often associated with CD4+ T-cell
lymphopenia.82 One or more of these conditions could be associated with mutations in the CIITA regulatory region.
pIV is also responsible for the inducible expression of MHCII on
extrahematopoietic cells, a widespread phenomenon that is intimately
associated with many normal and pathologic immune responses (reviewed
in a number of publications83-89). The strict dependence on pIV of both CD4+ T-cell development and inducible MHCII
expression suggests that these 2 features of the immune system may have
appeared simultaneously. It also suggests that ectopic MHCII expression
may play a more important role in the course of acquired immune
responses than was previously believed. We intend to address the role
of the inducible expression of MHCII genes in the presence of a normal CD4+ T-cell repertoire by crossing the pIV
We thank E. Reichmann for the antipankeratin serum and M. Kronenberg for CD1
Submitted June 24, 2002; accepted December 16, 2002.
Prepublished online as Blood First Edition Paper, December 27, 2002; DOI 10.1182/blood-2002-06-1855.
Supported by the Swiss National Science Foundation and the Gabriella Giorgi-Cavaglieri Foundation (W.R., H.A.-O.) and by the Ernst and Lucie Schmidheiny Foundation, the National Center for Competence in Research - Neural Plasticity and Repair (NCCR-NEURO), and the Swiss Multiple Sclerosis Foundation (W.R.). J.-M.W. is recipient of the MD/PhD fellowship from the Roche Research Foundation and of a fellowship generously provided by Professor A. F. Junod (Hopital Cantonal, Geneva, Switzerland).
W.R. and H. A.-O. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Walter Reith, Department of Genetics and Microbiology, University of Geneva, Medical School, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland; e-mail: walter.reith{at}medecine.unige.ch; and Hans Acha-Orbea, Ludwig Institute for Cancer Research, Lausanne Branch, Institute of Biochemistry, University of Lausanne, 155 ch des Boveresses, 1066 Epalinges, Switzerland; e-mail: hans.acha-orbea{at}ib.unil.ch.
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