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CUTTING EDGE |
: Implications for the Mechanism of pT Action1
*
Department of Molecular, Cell & Developmental Biology and
Section of Immunobiology, Yale University, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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, "pTb," is
derived from the pT locus by tissue-specific, alternative splicing.
pTb is coexpressed in the thymus with the previously
characterized form of pT (which we term pTa) and is
also expressed in peripheral cells without pTa. While
pTa acts to retain most TCR ß-chains intracellularly,
pTb permits higher levels of cell surface TCRß
expression and facilitates signaling from a CD3-TCRß complex. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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ß on peripheral T cells, the TCR ß-chain facilitates
recognition of pathogen-derived peptides presented on host MHC
molecules (1). Additionally, TCRß is part of the TCR-independent
pre-TCR that facilitates thymocyte maturation (2). Both TCRß and
the pre-TCR are complexed with CD35 chains that transduce
signals following receptor engagement (1). Beyond this, however,
pre-TCR structure and function are largely unresolved. For example,
surface pre-TCR expression on thymocytes is very low, provoking the
idea that rather than engaging a ligand at the cell surface, it may
signal from an inner cell compartment (3). Either possibility could
accommodate the fact that, to function, the TCR ß-chain must be able
to escape from the endoplasmic reticulum (4).
A third form of TCRß expression, which also is not well understood,
is the TCR-independent surface expression of TCRß on so-called
"ß-only" cells. Such cells were described in the periphery of
TCR-/- mice (5, 6), but may also exist in normal animals (see
below). ß-only cells, like other mature T cells, reportedly lack
pT (7). Hence, the nature of any partner chain for TCRß in these
cells is unresolved. Here, we show that cloned ß-only cells express a
second pT isoform, pTb, which is expressed in
vivo both by polyclonal ß-only cells and by thymocytes. The
expression pattern overlaps but is distinct from that of previously
described pT. Interestingly, transfection experiments demonstrate
that each isoform has functionally distinct effects on TCR ß-chain
expression and signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The cloning of T cell lines from TCR-/- splenocytes (8) has
been previously described (9). Clone H4ß expressed TCRß (not
TCR
) and grew extremely slowly, with or without feeder cells
(doubling time 
10 days).
Establishment of ß-only T cell hybridomas
TCR-/- splenocytes, stimulated for 3 days with Con A (2
µg/ml) (Sigma, St. Louis, MO) in Click’s medium containing 10% FCS
and 5 U/ml of IL-2 (human rIL-2; PharMingen, San Diego, CA), were fused
with the TCR-ß- BW5147 cell line
(10). Hybrids were selected in hypoxanthine-aminopterin-thymidine (HAT;
Life Technologies, Gaithersburg, MD), and cultures derived from single
colonies were analyzed by fluorescence-activated cell sorting (FACS)
and RT-PCR. Hybrid 1.10 was TCRß+, TCR-,
TCR-.
Cell staining, FACS, and analysis
Previously described methods (9) were used with the following
directly conjugated mAbs: phycoerythrin-conjugated anti-TCRß
(H57-597); anti-TCR (GL3); FITC-conjugated anti-CD4
(RM4-5); anti-CD8 (53-6.7) (all from PharMingen); and anti-HA
(12CA5) (Boehringer Mannheim, Indianapolis, IN).
Gene expression analyses
Previously described RT-PCR protocols (9) were used with pT
primers (7), hypoxanthine phosphoribosyltransferase (HPRT) primers (9),
and the following primers as listed: CD3 (5'-GTACAAGTGGATGGCAGC-3'
and 5'-TCACTTCTTCCTCAGTTG-3'); CD3 (5'-ATACCAGCGTCATGCATC-3' and
5'-GTATCTTCACGATCTCGA-3'); CD3
(5'-CGATGCCGAGAACATTGA-3' and
5'-CAGACTGCTCTCTGATTC-3'); CD3
and CD3
(5'-CAGAGCTTTGGTCTGCTG-3',
5'- TCTGCATATGCAGGGCAT-3', and 5'-CATGGACTCCACAGAGTG-3'); syk
(5'-CGGTACTTCTCCATACAC-3' and 5'-TTCAGGTCCTCAAAGGGT-3'); zap-70
(5'-ACCCTGTGAGCTGTGATA-3' and 5'-ACACCATAGCATCACGCA-3'); FcRI
(5'-TGATCTCAGCCGTGATCT-3' and 5'-TCAAAGCACAGAGGTGAC-3'), and TCRß
(5'-ATGAGCTGCAGGCTTCTCCTG-3' and 5'-TTCATAGGAGCTAACCCAGTA-3').
PCR products were cloned and sequenced with Thermo Sequenase (Amersham,
Arlington Heights, IL). Northern blot analysis with a
pTb-labeled probe was performed as described (11).
For RNase protection, a pTb cDNA probe was transcribed
in vitro from a T7 promoter (12).
Expression constructs and transfections
pTa and pTb cDNAs were
subcloned using BstxI/ApaI sites into the
eukaryotic expression vector pcDNA3 (Invitrogen, Carlsbad, CA).
pTa and pTb cDNAs lacking the
leader sequence were generated by PCR (Ref. 7; 5'-CTACCATCAGGCATCGCT-3'
and 5'-CTACCATCAGGGGAATCT-3') and cloned into pGEM-T (Promega,
Madison, WI), from which they were subcloned in-frame using
SalI/SacII sites into pDisplay (Invitrogen),
which provided a murine Ig 
-chain leader sequence linked to an HA
epitope. The TCR ß-chain expression construct was previously
developed in our laboratory from a diabetogenic CD4(+) ß T cell.
4G4 cells (107) (a TCR-ß- T hybridoma), maintained
in rapid growth phase, were pulsed at 960 µF, 320V with 20 µg of
plasmid in Capecchi’s HBS and transferred to 20 ml of Click’s
medium + 10% FCS. FACS analysis was undertaken 48 h later.
Stable transfectants were selected and maintained in 1.5 mg/ml of G418
(Life Technologies).
Signaling
Cells (4 x 105) were activated for 24 and 48 h in the presence of purified Abs (anti-CD3 and anti-I-Ad) previously coated to the plates (1 µg/ml, 12 h at 4°C). IL-2 secretion was tested in supernatants by ELISA (9).
Immunoprecipitation
Cells (5 x 106) were lysed on ice in 1 ml
of 150 mM NaCl, 1 mM MgCl2, 25 mM HEPES, pH 7.5, 1 mM of
Pefablock (Boehringer Mannheim, Indianapolis, IN), 10 µg/ml of
leupeptin, 10 µg/ml of antipain, and 0.5% Triton X-100. Lysates were
cleared for 10 min at 14,000 rpm, and supernatants were incubated with
1 µl of anti-HA Ab (HA.11, Babco, Richmond, CA) for 1 h on ice
with occasional shaking. Abs were precipitated with 25 µl of
Gamma-Bind beads (Pharmacia, Piscataway, NJ), and washed three times
with 1 ml of RIPA buffer. Proteins were eluted off beads by boiling for
5 min in reducing buffer and run on 15% SDS-PAGE gels in parallel with
a prestained standard (Broad Range; Bio-Rad, Richmond, CA). HA-tagged
pT was detected by Western blot using HA.11.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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-ß+ T cell clone from
TCR-/- mice
A small number of peripheral
CD3+CD4+CD8- cells of
TCR-/- mice express surface TCRß (6). A clone of such ß-only
cells, H4ß, was obtained by limiting dilution from TCR-/-
(H-2b) splenocytes. By FACS, H4ß was
surface-TCRß+, CD4+, TCR-,
CD8- (Fig. 1
A), and
CD3+CD69+ (not shown). The derivation of clone
H4ß took approximately 2 yr, in large part because of a slow growth
rate. This necessitated using RT-PCR rather than protein chemistry to
assess the components of the H4ß TCR. Signals for CD3-, -,
-, -, and - (Fig. 1B), were detected at
levels comparable with those of a control CD3(+) cell line, CTLL (not
shown). Signals were likewise detected for Zap-70, FcRI, and syk
(Fig. 1B). The expression by H4ß of surface TCRß,
all five CD3 chains, CD69, and of Zap-70 in excess to syk, is typical
of peripheral ß(+) T cells of normal mice.
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Because H4ß expresses surface TCRß without TCR, we tested
for expression of pT, the only other known partner for TCRß. 5'
and 3' pT-specific primers amplified a product of 
300 bp (Fig. 2A), composed of pT
exon 1 (5' untranslated (UT) region, leader peptide, and the first
three amino acids of the mature protein), exon 3 (connecting peptide
that provides the cysteine for dimerization with TCRß), and exon 4
(transmembrane region, cytoplasmic tail, and 3' UT region) (13) (Fig. 2C). The product lacked the 300-bp exon 2 that
encodes the major extracellular, Ig-like domain of pT. We termed the
novel isoform pTb and refer to the previously
characterized form as pTa (Fig. 2C).
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b expression, in the
absence of either pTa or TCR, in primary, polyclonal,
ß-only cells from TCR-/- mice (Fig. 2
, A and
B) and in a hybrid, 1.10, derived by fusion of
TCRß(+)- splenocytes (not shown). By contrast, RT-PCR detected
both pTb and pTa in the thymus (Fig. 2A). Sequencing the thymic products (Fig. 2A) confirmed the 600-bp band to be
pTa; the 300-bp band to be pTb; and the
500-bp band to be an artifactual hybrid of single strands of
pTa and pTb, respectively.
pT mRNA expression
A small pT isoform was previously detected in the thymus by
RT-PCR (7), but was reportedly not detectable by Northern blot or RNase
protection and hence was considered a possible PCR artifact. By
contrast, pTb could be detected by both methods
(Fig. 3, A and
B). For RNase protection, a radioactively labeled
pT RNA probe was generated in which exons 1 and 3 were contiguous.
Three hundred nucleotides of this probe should be protected by
pTb mRNA in which exons 1 and 3 are linked, but not by
pTa mRNA, in which a single-stranded, RNase-sensitive
gap would be created by failure of the pTb probe to bind
to pT exon 2. At the same time, the pTb probe
contained at its 5' end 40 bases of vector sequences that would not be
protected by pTb mRNA, allowing the 300-nt protected
band to be distinguished from undigested probe (340 nt) (Fig. 3A, lane P). The 300-nt protected
pTb-specific band was seen with thymus RNA
(lane T), and the ß-only hybridoma, 1.10 RNA
(lane F).
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B) pTa
expression was 10-fold greater than that of pTb in
thymus, whereas polyclonal ß-only cells expressed only
pTb. These quantitative data were highly consistent with
RT-PCR analyses of pTa and pTb in
different tissues (Fig. 2): hence, further RT-PCR analyses of pT
were performed. Again, thymus expressed more pTa than
pTb (Fig. 3C), while peripheral CD4(+)
TCR- cells from TCR-/- mice (a subset that would contain
ß-only cells) again expressed pTb but no
pTa. Interestingly, peripheral CD4(+) cells from normal
mice also expressed more pTb than pTa.
These cells may include murine counterparts of human CD4(+)CD3-
progenitors that reportedly express pTa (14).
Additionally, the strong pTb signal may reflect the
presence of ß-only cells in normal mice. Other peripheral subsets
from normal or TCR-/- mice expressed neither pTa
nor pTb.
Analysis of pT isoforms
Currently, the only known function of pT is to facilitate
ß-selection of thymocytes (15, 16), in which process pT is
hypothesized to stabilize surface TCRß (4, 17). We have detected
expression of both pT isoforms in thymocyte subsets undergoing
ß-selection (N. Douglas, D. F. Barber, and A. C. Hayday,
unpublished observations). Therefore, a transfection experiment was
undertaken to test whether pTa and
pTb had equivalent effects on TCRß expression.
(Although pTb lacks the Ig-like extracellular domain, it
retains the connecting peptide and within it the cysteine that allows
dimerization with TCRß).
To detect expression in transfected cells, pTa and
pTb were tagged with HA epitope before each was
individually cotransfected with TCRß into the TCR-deficient T cell
line, 4G4. In parallel, 4G4 cells were transfected with empty vector or
TCRß alone. Then, 48 h later, cells were examined for the
expression of both surface and intracellular TCRß and HA-tagged pT
(Fig. 4). A significant percentage of 4G4
cells transfected with TCRß alone expressed moderate but measurable
levels of surface TCRß (Fig. 4A). Invariably, when
cells were cotransfected with pTa, surface TCRß
expression was reduced (Fig. 4B). It was difficult to
trace redistribution of surface TCRß to the cytoplasm, because cells
transfected with TCRß alone or TCRß + pTa both
expressed intracellular TCRß (Fig. 4, J and
K). However, unlike pTa,
cotransfection with pTb did not measurably reduce
surface TCRß expression (Fig. 4C). The expression
of both forms of pT was confirmed by anti-HA reactivity,
predominantly of intracellular protein (Fig. 4, H and
I), and by Western blot (Fig. 4M).
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a and
pTb on TCRß expression were not due to the epitope
tag, the experiment was repeated with nontagged pT isoforms. Again,
surface TCRß expression was invariably reduced by coexpression with
pTa but not pTb. These different
capacities of pT isoforms and TCR to regulate surface TCRß
expression appear consistent with the expression of TCRß in vivo.
Thus, in double-negative thymocytes, pTa is in excess
and surface TCRß expression is barely detectable (17); in ß-only
cells, pTb is in excess and surface TCRß expression is
measurable but low (Figs. 1 and 2); and in mature T cells, TCRß pairs
with TCR, and surface TCRß expression is high. Although surface
pT expression in cotransfected cells was difficult to detect by FACS
(Fig. 4, E and F), the significance of
this is unclear, since the accessibility of the HA epitope in any of
the surface complexes is unknown.
To test further whether pTa and pTb had
distinct biologic effects, we examined TCR-mediated signaling in a
panel of 12 cell lines, stably transfected with combinations of TCRß
and pT (Table I). None of the cell
lines showed significant levels of surface CD3-TCR expression, but the
expression of various components was readily detected by RT-PCR (Table I). Anti-CD3 monoclonal 2C.11, which strongly activates cells
expressing stable TCR complexes, provoked significant IL-2 release from
only 3 cell lines (ß/300.2; T6 and T10), each of which expressed high
amounts of both TCRß and pTb RNA (Table I). No cells
expressing TCRß alone (ß8, ß9); TCRß with pTa
(ß/600.12; T2); pTa alone (ß/600.3) or
pTb with little or no TCRß (ß/300.3; ß/300.5; T3;
T9) responded strongly to anti-CD3 stimulation. Hence, in the
absence of TCR, strong signaling from the CD3 complex depended on
TCRß and pTb.
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a and pTb. pTa is
strongly expressed in the thymus and more weakly in some peripheral
cells; it retains significant amounts of TCRß intracellularly,
consistent with which it is poor at establishing CD3-associated cell
surface signaling. pTb is expressed in the thymus but
more strongly in some peripheral cells; it does not obviously retain
TCRß intracellularly, but rather enhances the capacity of transfected
TCRß to form signaling-competent, CD3-associated complexes. Based on
these data, one should consider the possibility that more than one type
of pre-TCR complex exists, with either opposing or complementary
effects on the cells that express them.
The suppression of surface TCRß expression by pTa
might seem to support the hypothesis that the pre-TCR transmits signals
from an intracellular compartment (3, 18). Alternatively, a role of
pTa may be to limit the expression of active, cell
surface, pre-TCR complexes that may contain pTb. This
proposal is rooted in the evidence that low/moderate avidity
interactions mediated by the TCR can activate thymocytes, while high
avidity interactions can induce apoptosis.
An indication that pTb can regulate thymocyte
development in vivo is provided by two gene-targeted mutations of
pT. One, generated by deletion of the transmembrane domain and the
pairing residue for TCRß, inhibits essentially all ß-selection of
cells (15); but the other, in which only pT exon 2 was disrupted, is
leaky with regard to ß-selection and allelic exclusion (19). It seems
possible that pTb expression was retained in the latter
animal and that this promoted thymocyte progression, albeit
inefficiently.
Finally, the different properties of pTa and
pTb are reminiscent of the distinct biologic effects of
the products of regulated alternative splicing at the IgCµ locus at
different stages of B cell maturation. One product facilitates IgM
functioning as a signaling-competent surface receptor that promotes B
cell maturation, while the other acts as part of a secreted Ag-binding
complex (20).
Note Added in Proof. It is possible that the 12-kDa
protein that we detect as a product of pTb (Fig. 4 M) is related to a 12-kDa pre-TCR-associated protein
reported by Takase, et al. (21).
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Acknowledgments |
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Footnotes |
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2 L.P. and L.W. contributed equally to this paper.
3 Current address: Section of Endocrinology, Dept. of Medicine, Yale University School of Medicine, New Haven, CT 06510.
4 Address correspondence and reprint requests to Dr. Adrian Hayday, Department of Molecular, Cell & Developmental Biology, Yale University, KBT 616, 219 Prospect Street, P.O. Box 208103, New Haven, CT 06520-8103. E-mail address:
5 Abbreviations used in this paper: CD3, cluster of differentiation Ags 3; FACS, fluorescence-activated cell sorter; nt, nucleotide; bp, base pairs; HA, haemagglutinin.
Received for publication February 20, 1998. Accepted for publication May 12, 1998.
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