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*
Transplantation and Immunobiology Group, John P. Robarts Research Institute, and
Departments of Microbiology and Immunology and of Medicine, University of Western Ontario, London, Ontario, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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and CD3 and
activation of several intracellular signaling cascades. Coordinate
activation of these pathways is dependent on Lck- and ZAP-70-mediated
tyrosine phosphorylation of a 36-kDa linker for activation of T cells
and subsequent recruitment of phospholipase C-
1, Grb2-SOS, and
SLP-76-vav. Here, we show that TCR partial agonist ligands can
selectively activate one of these pathways, the Ras-mitogen-activated
protein kinase pathway, by inducing recruitment of Grb2-SOS complexes
to incompletely phosphorylated p21 phospho-TCR-. This bypasses the
need for activation of Lck and ZAP-70, and for phosphorylation of the
linker for activation of T cells to activate Ras. We propose a general
model in which differential recruitment of activating complexes away
from transmembrane linker proteins may determine selective activation
of a given signaling pathway. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and CD3 chains by a Src kinase
(Lck or Fyn) (1, 2). In the presence of sustained
engagement of the TCR, ITAM phosphorylation is followed by recruitment,
phosphorylation, and activation of a Syk family kinase (ZAP-70), and
formation of multimolecular complexes that signal through different
intracellular pathways (3). Significant attention has been
focused on the link between the early phosphorylation events occurring
in the engaged TCR complex and the downstream signaling cascades
emanating from that receptor. The emerging paradigm is that the two
steps are linked by a heterogeneous group of transmembrane molecules
known as linkers (4). Two of these have already been
characterized: the linker for activation of T cells (LAT) (5, 6); and the TCR-interacting molecule (TRIM) (7).
Both are type III transmembrane proteins that are tyrosine
phosphorylated by coordinate action of a Src kinase and ZAP-70 after
TCR-mediated signaling. On phosphorylation, they recruit multiple
signaling molecules either directly (e.g., phospholipase C-1
(PLC1) or phosphatidylinositol 3-kinase), or indirectly (e.g., SOS,
vav, and Cbl), through Grb2 or SLP-76 (SH2 domain-containing 76-kDa
leukocyte protein) adapters. Thus, LAT and TRIM have a common function
in redistributing molecules to the cell membrane on early receptor
signaling, facilitating the interaction between enzymes and its
substrates. One of the intracellular signaling pathways activated by TCR engagement is the Ras-mitogen-activated protein kinase (MAPK) pathway (8, 9). Productive activation of this cascade causes translocation of several transcription factors and up-regulation of transcription of several genes that are required for proliferation and/or differentiation of activated T cells (10). Current evidence suggests that TCR-induced Ras activation requires cell membrane recruitment of SOS, a guanine-nucleotide-exchange factor (GEF) that converts the GDP-bound form of Ras into its active GTP-bound counterpart (8). Such a recruitment is likely determined by interaction between the SH2 domain in the Grb2 or Grb2-like Grap adapters with phosphorylated tyrosine residues in LAT (5, 11). Consistent with this model, it has been proposed that signaling through Ras in the context of coordinate activation of other signaling pathways (as induced by agonists of the TCR) requires tyrosine-phosphorylated LAT (5, 12). However, two observations suggest that Ras activation involves additional interactions: 1) phospho-LAT-dependent Grb2-SOS recruitment to the cell membrane is not sufficient for activation of Ras as seen in SLP-76-deficient cells after TCR ligation (13); 2) the Ras-MAPK pathway can be selectively activated in the absence of Lck and ZAP-70 kinase activities (Refs. 14, 15 ; M. L. Baroja and J. Madrenas, manuscript in preparation), e.g., after T cell stimulation with partial agonists of the TCR (14). Because phosphorylation of LAT and SLP-76 in mature T cells requires the activities of Lck and ZAP-70, it is logical to propose that TCR partial agonist-induced Ras-MAPK activation can occur through an alternative pathway independently of LAT phosphorylation. These alternative interactions between signaling molecules may determine distinct signaling patterns.
Although coordinate activation of different signaling cascades is
necessary for the development of effector functions by T cells,
selective activation of signaling pathways may have some biological
implications such as regulation of T cell survival (16).
In this sense, revealing the molecular basis of alternative pathways
for Ras activation may help us to understand how T cells can dissociate
signaling cascades and mount selective responses to different types of
Ag receptor ligands. Here, we report that TCR partial agonist ligands
utilize a phospho-LAT-independent pathway to activate the Ras-MAPK
pathway selectively. This occurs by recruitment of Grb2-SOS complexes
to an incompletely phosphorylated (p21) form of TCR-. On the basis
of these data, we propose a differential recruitment model for TCR
partial agonist signaling. According to this model, partial agonists of
the TCR induce incomplete phosphorylation of TCR- but no
phosphorylation of LAT. Under these conditions, Ras-activating
complexes are recruited to phospho-TCR-, and this correlates with
selective activation of the MAPK pathway. In contrast, the full
agonists of the TCR induce activation of Lck and ZAP-70 and subsequent
phosphorylation of LAT. This correlates with recruitment of
Ras-activating complexes to phospho-LAT and coordinate activation of
the MAPK pathway with other downstream signaling cascades.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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3C6 and A.E7 are CD4+ Th1 clones specific for pigeon cytochrome c fragment 81–104 bound to I-Ek molecules. These clones were kept in culture with repeated rounds of Ag stimulation followed by IL-2-driven expansion and rest for 10 to 14 days (17, 18). For consistency, all the values in this paper are representative of results using 3C6 T cells.
Monoclonal Abs
The following mAbs were used in these studies: 4G10 (a gift from
Dr. B. Drukker, Oregon Health Sciences University, Portland, OR) is a
mouse IgG2b mAb against phosphotyrosine; 6B10.2 is a mouse IgG1 mAb
against TCR- (Santa Cruz Biotechnology, Santa Cruz, CA); 81 is a
mouse IgG1 mAb against Grb2 (Transduction Laboratories, Lexington, KY)
used for immunoblotting of Grb2; and PE-labeled H1.2F3 is an Armenian
hamster IgG Ab against mouse CD69 (PharMingen Canada, Mississauga,
Canada). Rabbit polyclonal IgG sera against Grb2 (for
immunoprecipitation) and against SOS were purchased from Santa Cruz
Biotechnology. Anti-ACTIVE MAPK (Promega, Madison, WI) is a rabbit
antiserum against dual phosphorylated MAPK-derived peptide and
recognizes extracellular signal-related kinase (ERK) bands at 42/44 kDa
after cell activation. Dual phosphorylation of ERK-1 and ERK-2
correlates with activation of these enzymes (14). SHC was
immunoprecipitated or immunoblotted with a rabbit polyclonal immune
serum purchased from Transduction Laboratories. A sheep polyclonal IgG
serum against mouse SLP-76 was purchased from Upstate Biotechnology
(Lake Placid, NY). The rabbit immune sera against TCR-, ZAP-70, and
LAT used in these studies were kindly provided by Dr. L. E.
Samelson (Lymphocyte Signaling Unit, National Institute of Child Health
and Human Development, National Institutes of Health, Bethesda, MD).
The chimeric anti-CD3-fos and anti-CD4-jun molecules were
previously described (14) and were generated by Dr. J. Tso
(Protein Design Labs, Palo Alto, CA).
Cell stimulation and protein biochemistry
T cells (10–20 x 106/group) were
stimulated with heterofunctional Abs at a final concentration of 10
µg/ml, at 37°C, for 2, 5, or 10 min. Cells were pelleted in PBS
containing sodium o-vanadate (400 µM) and EDTA (400 µM)
and lysed in lysis buffer (1% Triton X-100, 150 mM NaCl, 10 mM Tris
(pH 7.6), 5 mM EDTA, 1 mM sodium o-vanadate, 10 µg/ml
leupeptin, 10 µg/ml aprotinin, 25 µM
p-nitrophenyl-p'-guanidinobenzoate), at 4°C for
30 min. Lysates were cleared of debris (14,000 rpm, 4°C, 10 min)
followed by immunoprecipitation of target molecules using Ab-coated
protein A- or G-Sepharose or agarose beads, for 2 h at 4°C. The
chimeric Abs cannot bind protein A because they lack an Fc portion.
Nevertheless, they may show some binding to protein G through the CH1
domain of the Fab fragment (19, 20, 21). However, the effect
of Fab binding on the specificity of TCR subunit immunoprecipitations
is minimal, as shown by controls in which the Abs were added to the
lysates before immunoprecipitation, by preclearing with protein
G-Sepharose or agarose beads alone, and by using protein A-Sepharose or
agarose beads for immunoprecipitations with appropriate Abs (see Fig. 3
). Beads were pelleted and resuspended in sample buffer, run in
SDS-PAGE, and immunoblotted with the indicated Abs. Signal detection
was performed by chemiluminescence (Roche Diagnostics, Laval, Canada).
Signal quantitation was done using a Bio-Rad GS-700 Image densitometer
and the MultiAnalyst version 1.0.2 software package (Bio-Rad, Hercules,
CA). Densitometry units for each band are expressed as OD adjusted by
surface (OD x mm2). Semiquantitative
analysis of protein association was reported as the ratio of
densitometric readings between specific treatments over background
levels in nonstimulated cells and corrected by cell number. As controls
for nonspecific reactivity of the blotting Ab, we used protein
G-Sepharose or agarose beads coated with the immunoprecipitating Ab in
the absence of cell lysate.
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Expression of the very early activation marker CD69 was examined on T cell clones (1.2 x 106 cells/group) after overnight culture without or with heterofunctional Abs at a final concentration of 10 µg/ml. Flow cytometric analysis was performed after cell staining for 45 min with PE-labeled mAb against mouse CD69 at 4°C.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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chains (p21 and p23 forms of phospho-)
and CD3-
, and activation of Lck and ZAP-70 kinase activities
(14, 18). In contrast, bivalent engagement of CD3 leads to
TCR-mediated signaling in a partial agonist mode, with incomplete
tyrosine phosphorylation of TCR- (only the p21 form of phospho-
is present) without phosphorylation of CD3- and without activation
of Lck and ZAP-70 (14). Despite the notable differences in
early signaling events, both agonist and partial agonist signaling
through the TCR lead to significant activation of the Ras-MAPK pathway
as illustrated by the appearance of dual phosphorylation and kinase
activity of ERK-1 and ERK-2 (Fig. 1a). As we have previously
reported (14), activation of ERK-1/2 is more transient
under partial agonist conditions when compared with that after agonist
signaling from the TCR and is undetectable after 30 min of stimulation.
Functionally, activation of the Ras-MAPK pathway under both patterns of
early TCR-mediated signaling translates into similar up-regulation of
CD69 expression, a downstream response that is dependent only on Ras
activation (12, 13, 22) (Fig. 1b). Therefore,
these data confirm that partial agonist ligands of the TCR induce a
biologically significant activation of the Ras-MAPK pathway.
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a) and the adapter protein
Grb2 (Fig. 2c). However, TCR partial agonists failed to
induce detectable tyrosine phosphorylation of LAT and formation of such
multimolecular complexes on LAT, above background control.
Specifically, TCR partial agonists did not induce recruitment of Grb2
to LAT (Fig. 2c), a critical step for the relocation of SOS
to the cell membrane. Semiquantitative evaluation of this result
indicates that 0.03% of total Grb2 in 3C6 T cells is associated to LAT
under agonist conditions, representing 10 times more than background
levels in resting cells or on partial agonist stimulation. Together,
these results support the claim that Ras-MAPK activation by TCR partial
agonists occurs without tyrosine phosphorylation of LAT.
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a) (30).
This may allow for recruitment of Ras-activating Grb2-SOS complexes to
an alternative site such as phosphorylated TCR-. According to our
model, phospho-LAT would be required for agonist-induced Ras activation
but not for partial agonist-induced Ras activation. We have recently
obtained further evidence supporting this model using Jurkat T cells
that lack functional ZAP-70 (P116 cells). In these cells, dimerization
of CD3 induces substantial ERK activation without significant
phosphorylation of LAT (M. L. Baroja and J. Madrenas, manuscript
in preparation).
Where could Ras-activating complexes be recruited in the absence of
phospho-LAT? A primary candidate as an alternative recruitment site of
Grb2-SOS complexes in the absence of phospho-LAT is the differentially
phosphorylated TCR- chain induced by partial agonists (17, 24, 31, 32, 33). An association between phospho-TCR- and Grb2 after
TCR ligation has been reported previously (32, 34), and
the association of Grb2 with TCR- has been shown in vivo with
constitutive expression of the p21 form of phospho-TCR- and after
abolishing the effect of CTLA-4 (35). Thus, we examined
the recruitment of Grb2-SOS to phospho-TCR- induced by agonists and
partial agonists of the TCR. As shown in Fig. 3, TCR-mediated signaling in agonist
pattern induced association between TCR- and Grb2. However, under
partial agonist conditions, there was a higher association between
TCR- and Grb2 than the one seen under agonist conditions (Fig. 3a). This was consistently detected after 10 min of T cell
stimulation. Semiquantitative analysis of three different experiments
for the amount of Grb2 associated to TCR- suggests that Grb2
associates to TCR- twice as much under partial agonist conditions as
under agonist conditions, and 
3 times above background levels. The
difference could not be explained by differences in the amount of
TCR- immunoprecipitated because the amount of TCR-
immunoprecipitated from nonstimulated samples and from stimulated ones
was similar (Fig. 3a). In addition, no detectable amount of
TCR- was immunoprecipitated by the stimulating chimeric
anti-CD3 Abs in the absence of immunoprecipitating Ab coating
agarose beads (Fig. 3b), indicating that detection of
TCR- in these samples is dependent on the immunoprecipitating Ab.
The TCR--Grb2 association was also detectable after performing Grb2
immunoprecipitations and immunoblots for TCR- (Fig. 3c).
The increased association between Grb2 and TCR- seen under partial
agonist conditions correlated with predominant induction of the p21
form of phospho-TCR- (Fig. 3d). In some experiments, we
found a low level of TCR--Grb2 association in nonstimulated cells
that correlated with a low level of p21 phospho- present in some
batches of T cells. Thus, Grb2 is recruited to phospho-TCR- after
TCR-mediated signaling in both agonist and partial agonist conditions,
but the magnitude of such an association is greater under partial
agonist conditions.
Grb2 could interact with phospho-TCR- directly or indirectly through
an intermediate adapter. Ravichandran et al. (34)
originally claimed that such an intermediate adapter role could be
played by SHC. This protein is tyrosine phosphorylated after TCR
ligation either by Lck, by a Syk kinase (ZAP-70 or Syk)
(36), or by Fyn (37). It can also interact
with ZAP-70 (38), and potentially recruit Grb2 through its
SH2 domain. The involvement of SHC as an intermediate molecule for the
TCR--Grb2 interaction on TCR signaling by partial agonists is very
attractive because SHC can bind TCR- ITAM3 when phosphorylated only
on the second tyrosine residue (39). This is one of the
three tyrosine residues that is phosphorylated in response to TCR
partial agonist ligands, the other two being the second tyrosine of the
first ITAM and the first tyrosine residue on the second ITAM. Thus, we
examined whether the association between Grb2 and TCR- occurred
through SHC. As shown in Fig. 4a, the magnitude of
TCR-SHC association was similar under agonist and partial agonist
conditions. On the other hand, the association between SHC and Grb2 was
dependent on tyrosine phosphorylation of SHC (Fig. 4, b and
c), with SHC being phosphorylated more under agonist
conditions of signaling than under partial agonist signaling (32, 34). As expected, the more tyrosine-phosphorylated SHC, the more
Grb2 was found in SHC immunoprecipitates (Fig. 4c).
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after partial
agonist induced signaling may occur, in part, independently from SHC.
This is suggested by higher levels of Grb2 associated to TCR- in
partial agonist signaling (Fig. 3a) with a similar amount of
SHC associated to TCR- in agonist and partial agonist signaling
(Fig. 4a). If the stoichiometry between Grb2 and SHC is 1:1,
then this observation implies that some Grb2 may associate directly
with monophosphorylated ITAM2 and -3 of TCR-, in addition to its
binding to monophosphorylated ITAM1 (24). The role of SHC
in the association between Grb2 and TCR- and its dependency on
tyrosine phosphorylation of SHC seen under partial agonist conditions
is consistent with previous observations in TCR agonist signaling
(24).
We have shown that Grb2 is proportionally recruited 5 times more to
phospho-LAT than to phospho-TCR- under agonist conditions. In
contrast, Grb2 is recruited 3 times more to phospho-TCR- than to LAT
under partial agonist conditions. Despite these differences, both
agonist and partial agonist signaling induced similar increase in the
association of SOS to Grb2 (Fig. 5). This
association is a necessary step for Ras activation (4, 40, 41, 42), further supporting a biological effect for both types
of Ras-activating complex recruitment.
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1
and the Ras-MAPK pathways following TCR ligation with agonist ligands
is SLP-76 (13). This is an adapter protein that is
recruited to phospho-LAT, most likely through a Grb2-like adaptor
(5, 43, 44). SLP-76 is also phosphorylated on multiple
tyrosine residues after T cell stimulation (45), possibly
by ZAP-70, likely determining its association with vav and nck and its
effects on cytoskeletal reorganization (46).
SLP-76-deficient T cells have a defect in PLC-1 and Ras-MAPK
activation (13), and SLP-76 knockout mice have a severe
block in early T cell development at the level of double-negative
thymocytes (47, 48). Interestingly, the defective
activation of Ras in SLP-76-deficient T cells occurs despite normal LAT
phosphorylation and abundant Grb2-SOS relocation to the cell membrane
after TCR ligation. The fine mechanism by which this occurs is not
clear, but it has been suggested that SLP-76 may contribute to the
formation of the multimolecular complexes centered on LAT
(13). We found that TCR partial agonists can induce low
but significant tyrosine phosphorylation of SLP-76 (Fig. 6). It is unknown at this time how SLP-76
is phosphorylated under partial agonist conditions, and what kinase is
responsible for such phosphorylation, because ZAP-70 is not active as a
kinase under these conditions. One possibility is that SLP-76 could
interact with one of the SH3 domains in Grb2 through a proline-rich
domain in its N terminus, fulfilling the requirement of Grb2-SOS-SLP-76
complex formation in the membrane to activate Ras. This would obviate
the need for phospho-LAT and be consistent with the absence of
phospho-SLP-76 in the LAT immunoprecipitates from T cells under partial
agonist conditions of stimulation (Fig. 2a). However, we
were not able to demonstrate convincingly the presence of Grb2 in
SLP-76 immunoprecipitates. One could argue that this is due to the
association of SLP-76 to the Grb2-related adaptor Gads rather than to
Grb2 as recently shown under agonist conditions of TCR-mediated
signaling (44). Nevertheless, we believe that this
scenario is unlikely because the Gads-SLP-76 association requires
phospho-LAT.
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and its effects on Ras-MAPK activation have remained
controversial (24). The discrepancies on these issues
reported with the use of T cell clones and hybridomas may reflect
distinct early TCR-mediated signaling in response to TCR engagement
(24, 32, 34). In agonist type of signaling,
phospho-TCR--Grb2-SOS association would not lead to additional Ras
activation if LAT is phosphorylated. On the other hand, under partial
agonist conditions of signaling, TCR--Grb2-SOS association would be
able to activate the Ras-MAPK pathway. It is not known whether the
involvement of SHC in the recruitment of Grb2 to TCR- has functional
implications different from those of direct recruitment of Grb2 to
TCR-.
Our data led us to propose that coordinate or selective activation of
the Ras-MAPK pathway occurs after recruitment of Grb2-SOS complexes to
phospho-LAT or to phospho-TCR- in response to agonists or partial
agonists of the TCR, respectively. TCR agonist ligands induce complete
phosphorylation of TCR- and subsequent phosphorylation of LAT. Under
these circumstances, multimolecular complexes form on phospho-LAT,
including Grb2-SOS, Cbl, PLC-1, and phosphatidylinositol 3-kinase.
These complexes determine coordinate activation of the Ras-MAPK pathway
concurrent with activation of other pathways such as the PLC-1
pathway. Some alternative recruitment of Ras-activating complexes to
the TCR- occurs under these conditions, but it may not be sufficient
to activate the Ras-MAPK pathway because of
interference/destabilization by ZAP-70-dependent activation of a
negative regulator such as cbl (28, 29) (our preliminary
observations). In contrast, TCR partial agonist ligands induce
incomplete phosphorylation of TCR- and fail to phosphorylate LAT.
Under these conditions, there is recruitment of Grb2-SOS complexes only
to the incompletely phosphorylated (p21) form of TCR-. Contrary to
agonist conditions of T cell activation, alternative recruitment of
Ras-activating complexes to incompletely phosphorylated TCR- would
be sufficient for selective activation of the Ras-MAPK pathway because
the lack of ZAP-70 activation prevents from negative regulation of
TCR--Grb2 association. This model emphasizes the role of linker
molecules in determining the location of specific signaling complexes
for coordinate activation of many signaling pathways, leading to the
development of effector T cell responses (16). Thus,
differential recruitment of some signaling complexes away from linker
molecules may be a general regulatory mechanism of the pattern of
activation of intracellular signaling pathways and enhance the
versatility of signaling from that receptor.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to J. Madrenas, John P. Robarts Research Institute, Room 2.05, P.O. Box 5015, 100 Perth drive, London, Ontario, Canada N6A 5K8. E-mail address:
3 Abbreviations used in this paper: ITAM, immune receptor, tyrosine-based activation motif; LAT, linker for activation of T cells; MAPK, mitogen-activated protein kinase; PLC1, phospholipase C-1; ERK, extracellular signal-related kinase.
Received for publication April 8, 1999. Accepted for publication June 7, 1999.
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References |
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M. Zubiaur, O. Fernandez, E. Ferrero, J. Salmeron, B. Malissen, F. Malavasi, and J. Sancho CD38 Is Associated with Lipid Rafts and upon Receptor Stimulation Leads to Akt/Protein Kinase B and Erk Activation in the Absence of the CD3-zeta Immune Receptor Tyrosine-based Activation Motifs J. Biol. Chem., January 4, 2002; 277(1): 13 - 22. [Abstract] [Full Text] [PDF]
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