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Department of Microbiology and Immunology, University of California, San Francisco, CA 94143;
Department of Medical Biochemistry and Medical Research Council Center for Molecular and Cellular Biology, University of Stellenbosch, Tygerberg, South Africa;
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, Illkirch, France; and
§
Institute for Genetics, University of Köln, Köln, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The developmental significance of many other cell surface structures
that are induced during thymocyte development is less obvious. An
example of this is the CD5 molecule, a 68-kDa glycoprotein that is
substantially up-regulated soon after thymocytes receive the pre-TCR
signal (6). CD5 is expressed on all thymocytes and T cells
and is also found on B-1 cells. Interestingly, the level of CD5 that is
expressed on thymocytes and T cells is in part determined by the
magnitude or form of signals delivered by the TCR-
ß
(6). Thus, CD5 expression is typically lower on
CD4+CD8+ immature
thymocytes than on mature
CD4+CD8- or
CD4-CD8+ single-positive
cells that have received an TCR-ß signal. Various potential
ligands for CD5 have been described on B cells (7, 8, 9), but
the true identity of the physiologically relevant ligand(s) remains to
be established (10).
When cross-linked with mAbs, CD5 delivers a signal to T cells that augments their proliferation in response to TCR stimulation (11, 12, 13, 14). This type of effect suggests that CD5 could perform a costimulatory or amplification role during certain types of T cell interactions. For instance, there is evidence that B cell responses may be influenced by binding between CD5 on T cells and a ligand on B cells (9). Paradoxically, however, the absence of CD5 confers a hyper- rather than hyporesponsive phenotype to thymocytes when they are stimulated through their TCRs (15). Moreover, CD5-deficient mice have normal numbers of T cells and B cells and can mount robust immune responses to a variety of antigenic challenges (16). These and other findings have implicated CD5 as a negative regulator of Ag receptor signaling during thymocyte repertoire selection.
In this paper we present the results of studies addressing the impact of CD5 on the selection and responses of CD4 lineage T cells. Whereas previous work had focused primarily on CD8 lineage thymocytes (15), the new data show that CD5 is also a negative regulator of TCR signaling in the CD4 lineage. Furthermore, we show that in addition to thymocytes, CD5 affects TCR responses in mature T cells. Cumulatively, the data support a general role for the CD5 molecule in negative regulation of Ag receptor signal transduction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mAbs used in the experiments included unconjugated or
fluorochrome-conjugated anti-CD3
(145-2C11), anti-CD69
(H1.2F3), and anti-CD24 (M1/69) from PharMingen (San Diego, CA);
anti-CD4 (CT-CD4), anti-CD8 (CT-CD8), anti-CD90
(CT-Thy1), and anti-CD5 (Ly-1.2), from Caltag (Burlingame, CA); and
anti-BrdU4 mAb
from Becton Dickinson (San Jose, CA.). The mAb specific for the
DO.11.10 clonotypic receptor (KJ-126) (17) was purified
from culture supernatant and biotinylated according to standard
procedures. Biotinylated mAbs were detected with streptavidin-TriColor
(Caltag) or streptavidin-Spectral Red (Southern Biotechnology
Associates, Birmingham, AL).
Cell lines
The 171.1 T cell hybridoma recognizes a hen egg lysozyme (HEL) peptide (NLANIPASALLSSDI, residues 74–88) presented by I-Ab (18). It does not express detectable CD5 by flow cytometry. The T cell hybridoma 2A4.3 was generated by immunizing CD5° mice s.c. in the hind foot pads using a 1/1 emulsion of OVA (1 mg/ml) in CFA (Life Technologies, Grand Island, NY). Popliteal lymph nodes were harvested 10 days after immunization and activated in vitro with 20 µg/ml OVA and 100 U/ml rIL-2 (Genzyme, Cambridge, MA) for 4 days with syngeneic splenocytes before polyethylene glycol-mediated fusion to the BW5147 cell line. Hybridomas were selected in hypoxanthine-aminopterin-thymidine for 7 days before testing for reactivity to OVA, as determined by IL-2 secretion, and for loss of CD5 expression. The CD5° hybridoma 2A4.3 lost responsiveness to OVA after several rounds of subcloning, but maintained the ability to secrete IL-2 upon anti-CD3 mAb stimulation.
Retroviral gene transfer
A mismatch primer (5'-ctgacgctgttatttctgacg-3') was used to
insert a termination codon in a CD5 cDNA in place of the codon for
lysine 389 of the mature CD5 polypeptide. The 389
form of CD5
encoded by the mutant cDNA lacks all but the 11 membrane-proximal
residues of the cytoplasmic tail. The cDNAs for the green fluorescent
protein (GFP), CD5-WT, or 389 were cloned into the Moloney murine
leukemia retroviral vector LZRSpBMN-Z in place of
lacZ gene (gift from Dr. Garry Nolan, Stanford University,
Stanford, CA). Viral supernatants were produced by transient
transfection in 293T cells with vectors expressing retroviral gag and
pol proteins and the vesicular stomatitis virus glycoprotein (gifts
from Dr. Derya Unutmaz, New York University, New York, NY), and these
were used to infect either 171.1 or 2A4.3 cells for 6 h in the
presence of 8 µg/ml polybrene. Infected cells were matched for
expression of CD3, CD4, and CD5 by electronic cell sorting on a FACS
Vantage (Becton Dickinson, San Jose, CA) or a MoFlo cytometer
(Cytomation, Ft. Collins, CO).
Flow cytometry
Single-cell suspensions were prepared from lymph nodes and thymuses and incubated with the appropriate Abs for 30 min at 4°C. Cells were washed twice in 1x PBS/0.3% BSA/0.01% NaN3 between staining steps and before analysis. BrdU-labeled cells were detected by staining with an anti-BrdU Ab as previously described (19). ß-Galactosidase-expressing cells in CD4/ß-gal mice were detected by staining with fluorescein digalactopyranoside as previously described (20). Scatter-gated cells (1 x 104 to 1 x 105) were analyzed using a Becton Dickinson FACScan and CellQuest software (Becton Dickinson). For electronic sorting, cells were stained under sterile conditions using 10% FCS in DMEM (Life Technologies) as wash buffer.
T cell assays
Lymph nodes were harvested from DO.11.10 TCR transgenic control or CD5-deficient mice and incubated with a mixture of anti-CD8 and anti-B220 microbeads (Miltenyi Biotech, Auburn, CA). Cells were then purified by magnetic separation according to the manufacturer’s protocol (Miltenyi Biotech). The purity of the resulting populations was assayed by flow cytometry and was typically 80–90%. CD4+ T cells (1 x 105) were incubated with 2.5 x 105 T cell-depleted syngeneic splenocytes in the presence of varying concentrations of the OVA323–339 peptide. Cultures were incubated at 37°C for 72 h in 5% CO2 and pulsed with [3H]thymidine (Amersham, Arlington Heights, IL) during the last 18 h of the culture.
171.1 cells were stimulated with T-depleted C57BL/6 spleen cells in the presence of varying concentrations of HEL peptide. The IL-2 production was determined by capture ELISA (PharMingen) from supernatants harvested at 24 h. 2A4.3 cells were incubated on anti-CD3 (2C11-145)-coated 96-well plates for 24 h before IL-2 production was determined by ELISA.
The frequency of allo-MHC class II-reactive T cells in various mutant mice was determined as previously described (21). In brief, 2 x 106 lymph node responder cells were incubated in vitro with 5 x 106 irradiated (2000 rad) stimulator spleen cells for in 24-well plates. BrdU (5 µg/ml) was included in the cultures so that cells undergoing DNA synthesis would be labeled. Cytokinesis was blocked by the inclusion of 1 µM colchicine. Alloreactive CD4 lineage cells were quantified after 3 days by three-color FACS analysis using anti-BrdU, -CD8, and -CD3 mAbs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study the influence of CD5 on the development and function of
CD4 lineage cells, we crossed CD5-deficient mice to transgenic mice
expressing the DO11.10 TCR. This TCR is specific for a peptide from
chicken OVA presented by I-Ad, but it is also
weakly alloreactive against I-Ab
(22). In H-2d mice, there is
positive selection of thymocytes bearing this TCR into the CD4 lineage
(23, 24). In contrast, TCR transgenic
H-2b mice show decreased thymic cellularity,
reduced numbers of peripheral CD4+ T cells,
down-regulation of TCR levels, and an overabundance of double-negative
T cells. H-2bd DO11.10 TCR transgenic mice have
an intermediate phenotype, with sizeable thymuses, increased numbers of
double-negative T cells, and slight down-regulation of TCR levels (Fig. 1
) (24, 25).
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, A and
C). This apparent enhanced deletion of thymocytes did not
block the development of CD4 lineage cells. Rather, there was a trend
toward more CD4+CD8- cells
in the thymuses of these mice than in CD5-expressing control mice (Fig. 1, A and C). There were also abundant
clonotype-expressing CD4+ T cells in the lymph
nodes of the CD5° TCR transgenic mice (Fig. 1B). Thus, CD5
deficiency in H-2d mice leads to pronounced
negative selection of many DO11.10 TCR transgenic thymocytes, while
still allowing for efficient positive selection of clonotype-bearing
cells.
In contrast to the H-2d phenotype, CD5 deficiency
appeared to enhance selection against thymocytes with high levels of
the DO11.10 TCR in both homozygous and heterozygous
H-2b mice. This enhancement was evident in at
least two ways. First, the absence of CD5 correlated with lower
expression of CD3 and the transgenic clonotype on CD4 lineage
thymocytes and T cells (Fig. 1A). This down-regulatory
effect was most pronounced in H-2bd mice, but was
also apparent in H-2bb mice. Second, there were
significantly more double-negative clonotype-expressing peripheral T
cells in H-2bd CD5° mice (Fig. 1B
and data not shown). Such double-negative T cells have been previously
observed in several other TCR transgenic settings that feature
prominent negative selection (26). Thus, by these
criteria, the negative selection phenotype characteristic of
H-2b DO11.10 TCR transgenic mice appeared to be
more severe in the absence of CD5.
Cumulatively, the above observations on DO11.10 TCR transgenic mice indicate that CD5 influences the selection of CD4 lineage T cells. Moreover, the data are consistent with a role for CD5 in negative regulation of TCR signal transduction. In both H-2d and H-2b mice, the loss of CD5-mediated negative regulation enhances negative selection. In the latter, but not the former, the impact of CD5 deficiency is sufficient to preclude the selection and/or survival of cells that retain high levels of the transgenic TCR heterodimer. These data are similar to those previously reported for the variable impact of CD5 deficiency on the selection of CD8 lineage T cells (15)
CD4 lineage development in CD4°CD5° mice.
The development of the CD4 lineage is markedly impaired, but not
completely disabled, by the absence of CD4 (27, 28).
Because CD4 is a positive regulator of TCR signal transduction, it
seemed possible that the loss of CD5-mediated negative regulation might
partially suppress the CD4° phenotype and rescue the development of
some Th cells. Flow cytometric analysis of thymocytes and peripheral T
cells showed a phenotype consistent with this expectation.
Specifically, there were typically 3-fold more mature (i.e.,
CD24low) CD4 lineage (i.e.,
CD8-CD3high) thymocytes
(Fig. 2A) and 2-fold more
peripheral CD8- T cells (Fig. 2B) in
CD4°CD5° than in CD4° mice. To confirm that the
CD8- thymocytes belonged to the CD4 lineage, we
also established crosses between CD5° mice and mice carrying a
ß-galactosidase transgene inserted directly into the CD4 locus
(20). The CD4/ß-galactosidase knockin allele
(CD4L) in these mice does not encode a functional
CD4 protein, but instead expresses ß-galactosidase in place of CD4.
ß-Galactosidase expression in mature thymocytes and T cells from
these mice can therefore be used as a marker for the CD4 lineage. As
shown in Fig. 2C, the absence of CD5 increased the fraction
of CD24low TCRßhigh
CD8- cells in the thymuses of mice that were
homozygous for the CD4/ß-galactosidase knockin allele
(CD4L/L). CD8-, but not
CD8+, mature thymocytes in
CD4L/L CD5° mice were clearly enriched for
expression of the ß-galactosidase reporter and therefore belonged to
the CD4 lineage.
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D) or
CD3highCD8- (not shown)
thymocytes. Thus, the apparent increase in the representation of the
CD4 lineage in the CD4°CD5° mice was due to enhanced
development.
To confirm that the peripheral CD8- T cells were
functional CD4 lineage cells, we compared the frequency of allo-class
II reactive cells in the
CD8-CD3+ populations of
wild-type, CD4°, and CD4°CD5° mice. As stimulator cells in these
experiments, we used irradiated allogeneic spleen cells from C57BL/6
congenic mice carrying either the bm1 or bm12 mutations (in
Kb or I-Ab, i.e., MHC class
I or MHC class II, respectively) (29). Purified
CD3+CD8- T cells from the
various mice were incubated in vitro with bm1, bm12, or C57BL/6
stimulator cells in the presence of colchicine and BrdU. Alloreactive
cells were then identified by FACS using an anti-BrdU Ab to detect
BrdU incorporated into their DNA. Because cell division was blocked by
the action of colchicine (21), it was possible to use BrdU
incorporation as a direct measure of the frequency of alloreactive
cells in the starting population. As shown in Fig. 3B, the CD8 lineage in all
mice included T cells with reactivity for the bm1, but not the bm12,
mutation. Conversely, wild-type CD4 lineage T cells showed the inverse
pattern of reactivity (Fig. 3A). Although, the CD4°
animals showed virtually no reactivity for bm12, the
CD3+CD8- T cells in the
CD4°CD5° mice included a frequency of bm12-reactive cells similar
to that observed in the wild-type CD4 lineage (Fig. 3A).
Importantly, the CD3+CD8-
population did not react to stimulation with bm1 cells (Fig. 3B). These observations are wholly consistent with the
interpretation that the
CD3+CD8- population is MHC
class II restricted in its reactivity and therefore belongs to the CD4
lineage. Thus, the absence of CD5 potentiates the development of MHC
class II-restricted CD4 lineage cells in CD4° mice.
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To examine the influence of CD5 on TCR signaling in mature T
cells, we adopted two approaches. The first of these was to compare the
peptide-specific responses of DO11.10 CD4+ T
cells from CD5° and CD5-expressing mice. As shown in Fig. 4A, purified CD5° transgenic
CD4+ T cells responded more strongly to lower
concentrations of the OVA peptide than did control T cells. For these
experiments, we used cells from mice that were homozygous for the
H-2d haplotype; such cells do not show the
down-regulation of cell surface TCR levels that is evident in mice
carrying the H-2b haplotype. Thus, this
experiment shows that loss of CD5 function correlates with enhanced
reactivity for TCR ligands in mature peripheral T cells.
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, B and C, the
presence of wild-type CD5 in both cell lines correlated with reduced
responsiveness to Ag receptor engagement. Cell lines expressing the
mutant form of CD5 showed similar responses to the parental cell lines.
Thus, gain of CD5 function negatively regulates Ag receptor signaling
in these two T cell hybridomas, and this effect depends on the presence
of the CD5 cytoplasmic domain. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In a previous report, mice expressing MHC class I-restricted TCRs showed variable responses to the absence of CD5 (15). Here, the added sensitivity gained through CD5 deficiency was apparently enough to improve selection for the H-Y TCR, but was too great for selection of the P14 TCR. Because the DO11.10 TCR is weakly alloreactive against I-Ab (22), it is perhaps not surprising that the loss of negative regulation by CD5 would augment the slight H-2b negative selection phenotype (24, 25) and reduce the frequency of clonotype-expressing cells.
In contrast to the H-2b phenotype,
H-2d DO11.10 TCR transgenic mice showed
characteristics of enhanced negative selection in the context of
persistent positive selection. Thus, the loss of CD5 caused an obvious
reduction in the number of
CD4+CD8+ TCR transgenic
cells present in H-2d thymuses, but it did not
select against high levels of the DO11.10 clonotype. Furthermore, there
were often more CD4+CD8-
cells present in the CD5° thymuses than in control thymuses (Fig. 1C). One possible interpretation of these data is that, as
argued for H-2b mice, CD5 deficiency enhances TCR
signaling in response to thymic I-Ad ligands. The
resultant increase in the TCR signal is then sufficient to increase the
probability that a CD4+CD8+
thymocyte will be deleted, but is insufficient to select efficiently
against high levels of the TCR clonotype. A similar split phenotype of
effective positive selection in the context of reduced thymic
cellularity occurs in other TCR transgenic mice, such as those
expressing the 2C receptor on an H-2b background
(30, 31). CD5 deficiency has no obvious effect on the
representation of CD4+CD8+
cells in nontransgenic thymocytes (16), suggesting that it
is not normally involved in regulating the expansion of clones after
they have received the pre-TCR signal. Thus, the reduction in
CD4+CD8+ cells observed in
CD5°DO11.10 TCR transgenic mice is most likely the result of
MHC-dependent negative selection.
As an additional demonstration of the developmental significance of
CD5, we showed that loss of CD5 could partially suppress the block of
development of the CD4 lineage in CD4° mice. Rescue of CD4 lineage
cells was evident in both the thymus and the periphery, although,
interestingly, the effect was of greater apparent magnitude in the
thymus (
3-fold vs 2-fold). Signaling thresholds for survival in the
thymus may well be distinct and regulated differently from those in the
periphery. Therefore, it seems feasible that the gain in signaling
responsiveness caused by loss of CD5 could facilitate thymic
development and peripheral survival/expansion to varying degrees.
Alternatively, it is possible that CD4 lineage cells do not exit the
thymus efficiently in the CD4°CD5° mice and perhaps accumulate to
some extent in the medulla. Our BrdU labeling studies indicate that the
development of CD4 lineage cells is enhanced by the loss of CD5 in
CD4° mice, but they do not address the potential for accumulation in
the medulla. Nonetheless, although we have not yet explored the basis
for the difference in representation of CD4 lineage cells in the thymus
vs the periphery, it is apparent that the absence of CD5 affords a
substantial cellular and functional rescue of the CD4 lineage. In this
respect, the findings are consistent with the proposed negative
regulatory function for CD5.
Perhaps the most direct demonstration of CD5-mediated negative
regulation came from the T cell hybridoma studies (Fig. 4), in which
the expression of CD5 suppressed TCR-dependent responses. Negative
regulation in this setting did not occur in the absence of the CD5
cytoplasmic tail, suggesting that the effect depended on intracellular
interactions mediated by CD5. The nature of these interactions is
currently a matter of speculation. CD5 may associate with several
cytoplasmic proteins that have been implicated in various forms of
negative regulation. One of these is SHP-1 (Src homology 2
domain-bearing protein tyrosine phosphatase-1) (32), a
protein tyrosine phosphatase that negatively regulates signaling from a
variety of hemopoietic receptors, including NK inhibitory receptors and
the B cell receptor (33, 34, 35, 36). Dominant negative forms of
SHP-1 impair TCR signaling (37), and thymocytes from
SHP-1-defective Mev mice are hyperproliferative
(32). Recent data suggest that the tyrosine residue at
position 378 of CD5 may be important for association with SHP-1 and may
be required for negative regulatory activity (38). Our
data appear somewhat difficult to reconcile with this conclusion,
because tyrosine 378 is retained in a tailless CD5 mutant that does not
negatively regulate TCR responses in the hybridomas we have tested.
Although we can coprecipitate SHP-1 with wild-type CD5 from lysates of
pervanadate-stimulated T cell hybridomas, we do not detect SHP-1
associating with the tailless mutant (unpublished observations).
Additional experiments are required to explore further the potential
significance of SHP-1 for CD5-mediated negative regulation.
In addition to SHP-1, several other signaling molecules may associate
with the cytoplasmic tail of CD5. These include the protein kinase
casein kinase II (CK2), RasGAP, p116cbl, Tctex,
Ca2+/calmodulin-dependent kinase II
, and
phosphatidylinositol-3-kinase (13, 39, 40, 41, 42). In most cases,
there is at least the potential for the associated protein to confer a
negative regulatory function. For instance, although CK2 has a positive
role in regulating the cell cycle (43, 44, 45), it may also
negatively regulate both MEK1 activation (46) and AP-1
activity (47). RasGAP down-regulates Ras signaling by
catalyzing GTP hydrolysis of activated RasGTP (48).
Similarly, through a pathway that involves rap1,
p116cbl also down-regulates Ras activity
(49) and disruption of the c-cbl gene causes
enhanced T cell proliferation (50). Finally, the
activation of NF-AT is negatively regulated by
phosphatidylinositol-3-kinase activity in T cells
(51). The significance of any or all of these associations
for negative regulation by CD5 is currently unclear and awaits more
selective mutagenesis of the CD5 cytoplasmic tail.
Regardless of the mechanism involved, the immunological significance of negative regulation mediated by CD5 is somewhat obscure. The data presented here and previously show that the selection of T cells occurs differently in the presence or the absence of CD5. The repertoire of TCRs carried by CD5° T cells is therefore likely to be distinct from that of wild-type T cells. Nonetheless, CD5° mice have a full complement of T cells with diverse specificities capable of mediating several types of protective immune responses (16) (C. Peña-Rossi and N. Killeen, our unpublished data). The CD5 molecule is conserved between evolutionarily distant organisms, especially in the cytoplasmic tail (52), suggesting that there is a distinct selective advantage conferred by its function. Given the absence of obvious immunodeficiency in CD5° mice, the nature of this advantage has not yet been established. It seems probable, however, that the change in the TCR repertoire caused by loss of CD5 represents a significant survival risk under certain circumstances. At least two types of approaches could provide further information on the true significance of the CD5 advantage. One is to explore a range of pathogenic challenges in search of ones that would selectively overcome CD5° hosts. A successful immune response to such challenges would then presumably involve either the direct extrathymic involvement of the CD5 molecule or a critical role for cells that do not get selected without CD5. The other is to understand exactly how the TCR repertoire might be compressed, expanded, or shifted without CD5, i.e., to get a better sense of the overall complexity and potential specificity of the CD5° T cell population.
There is accumulating evidence that thymocytes are more sensitive to stimulation through their TCRs than mature T cells (53, 54, 55, 56). Such enhanced sensitivity is presumably essential for the efficient elimination of autoreactive thymocytes and for positive selection. The mechanisms that allow for enhanced sensitivity are unclear, but could well involve developmentally regulated changes in the expression of molecules such as CD5. Consistent with this view, double-positive thymocytes express less CD5 than mature single-positive cells. Lower expression of CD5 coupled with the increased expression of positive regulators such as the Syk tyrosine kinase (57) may be essential in establishing a hypersensitive state at the double-positive stage. The complete absence of CD5 in CD5° mice appears to accentuate this state and thereby may bias repertoire selection against cells that make efficacious, but still selectable, engagements with thymic peptide/MHC ligands.
Although the data in this and a previous report (15) reveal a clear role for CD5 in repertoire selection, they also re-emphasize the potential for productive T cell development in its absence. Thus, it is reasonable to conclude that CD5 is largely dispensable for the development of T cells. This, however, does not exclude either the above-mentioned effect on repertoire selection, or the possibility that other molecules share overlapping functions with CD5. An obvious candidate in this last role would be CD6, which is a glycoprotein that is structurally very similar to CD5, at least in its extracellular portion (58, 59). The genes encoding CD5 and CD6 are closely linked in the genome (60, 61) and share a related pattern of expression (62, 63). Thus, it is possible that CD6 may partially compensate for CD5 deficiency in CD5° mice. If so, the true significance of the function that CD5 performs during T cell development and immune responses may only be apparent in mice that lack the expression of both CD5 and CD6.
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Acknowledgments |
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Footnotes |
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2 C.P.-R, and L.A.Z. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Nigel Killeen, Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0414. E-mail address:
4 Abbreviations used in this paper: BrdU, bromodeoxyuridine; HEL, hen egg lysozyme; GFP, green fluorescent protein; CK2, casein kinase II; SHP-1, Src homology 2 domain-bearing protein tyrosine phosphatase-1.
Received for publication July 30, 1999. Accepted for publication October 6, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß T cells that contains autoreactive cells. J. Exp. Med. 174:1001.. Eur. J. Immunol. 28:2167.[Medline]
. J. Immunol. 161:5164. transgene-induced murine lymphoma: relation to theileriosis in cattle. Science 267:894.. Science 276:952.This article has been cited by other articles:
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  K. Laky and B.J. Fowlkes Presenilins regulate {alpha}{beta} T cell development by modulating TCR signaling J. Exp. Med., September 3, 2007; 204(9): 2115 - 2129. [Abstract] [Full Text] [PDF]
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|
 H. G. Kasler and E. Verdin Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes Mol. Cell. Biol., July 15, 2007; 27(14): 5184 - 5200. [Abstract] [Full Text] [PDF]
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 |
|
 G. Friedlein, F. El Hage, I. Vergnon, C. Richon, P. Saulnier, Y. Lecluse, A. Caignard, L. Boumsell, G. Bismuth, S. Chouaib, et al. Human CD5 Protects Circulating Tumor Antigen-Specific CTL from Tumor-Mediated Activation-Induced Cell Death J. Immunol., June 1, 2007; 178(11): 6821 - 6827. [Abstract] [Full Text] [PDF]
|
|
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N. J. Hassan, S. J. Simmonds, N. G. Clarkson, S. Hanrahan, M. J. Puklavec, M. Bomb, A. N. Barclay, and M. H. Brown CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76. Mol. Cell. Biol., September 1, 2006; 26(17): 6727 - 6738. [Abstract] [Full Text] [PDF]
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G. Dorothee, I. Vergnon, F. El Hage, B. L. M. Chansac, V. Ferrand, Y. Lecluse, P. Opolon, S. Chouaib, G. Bismuth, and F. Mami-Chouaib In Situ Sensory Adaptation of Tumor-Infiltrating T Lymphocytes to Peptide-MHC Levels Elicits Strong Antitumor Reactivity J. Immunol., June 1, 2005; 174(11): 6888 - 6897. [Abstract] [Full Text] [PDF]
|
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R. C. Axtell, M. S. Webb, S. R. Barnum, and C. Raman Cutting Edge: Critical Role for CD5 in Experimental Autoimmune Encephalomyelitis: Inhibition of Engagement Reverses Disease in Mice J. Immunol., September 1, 2004; 173(5): 2928 - 2932. [Abstract] [Full Text] [PDF]
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E. Janssen, M. Zhu, B. Craven, and W. Zhang Linker for Activation of B Cells: A Functional Equivalent of a Mutant Linker for Activation of T Cells Deficient in Phospholipase C-{gamma}1 Binding J. Immunol., June 1, 2004; 172(11): 6810 - 6819. [Abstract] [Full Text] [PDF]
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|
 |
|
 Y. Yang, C. H. Contag, D. Felsher, C. M. Shachaf, Y. Cao, L. A. Herzenberg, L. A. Herzenberg, and J. W. Tung The E47 transcription factor negatively regulates CD5 expression during thymocyte development PNAS, March 16, 2004; 101(11): 3898 - 3902. [Abstract] [Full Text] [PDF]
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C. Brossard, M. Semichon, A. Trautmann, and G. Bismuth CD5 Inhibits Signaling at the Immunological Synapse Without Impairing Its Formation J. Immunol., May 1, 2003; 170(9): 4623 - 4629. [Abstract] [Full Text] [PDF]
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|
 I. Gimferrer, M. Farnos, M. Calvo, M. Mittelbrunn, C. Enrich, F. Sanchez-Madrid, J. Vives, and F. Lozano The Accessory Molecules CD5 and CD6 Associate on the Membrane of Lymphoid T Cells J. Biol. Chem., February 28, 2003; 278(10): 8564 - 8571. [Abstract] [Full Text] [PDF]
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 N. G. Singer, D. A. Fox, T. M. Haqqi, L. Beretta, J. S. Endres, S. Prohaska, J. R. Parnes, J. Bromberg, and R. M. Sramkoski CD6: expression during development, apoptosis and selection of human and mouse thymo |
0.0003, by
Student’s paired t test). The average percentages of
CD4-CD8- T cells in H-2bd DO11.10
CD5° and control lymph nodes were 60.6 and 23.5%, respectively
(p 
) and CD5° (•) thymocytes from mice on the indicated
MHC backgrounds. The average numbers of
CD4+CD8+ thymocytes in H-2dd CD5°
or control mice were 65.4 x 106 and 191 x
106, respectively (p 
), or
B6.C-H2bm1/ByJ (bm1; •) mice. Cultures
were treated with colchicine to block cell division as described in
Materials and Methods. Activated BrdU-labeled CD4
(A) and CD8 (B) lineage T cells were
enumerated by FACS as fractions of the total CD4
(CD3+CD8-) or CD8
(CD3+CD8+) lineages, respectively. Each symbol
denotes a determination for cells from an individual mouse. The data
shown are from one experiment that is representative of four others.
CD5° mice were indistinguishable from wild-type mice in this assay
(not shown).
). Results are from one representative experiment of three (2A4.3)
and six (171.1) performed.