Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota
Correspondence: Yoji Shimizu, Dept. of Laboratory Medicine and Pathology, University of Minnesota Medical School, MMC 334, 312 Church St. SE, Minneapolis, MN 55455. E-mail: shimi002{at}tc.umn.edu
 TOP ABSTRACT INTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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Key Words: tyrosine kinase • cytoskeleton • phosphatidylinositol 3-kinase • Itk
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TOPABSTRACTINTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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TOPABSTRACTINTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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chain. These phosphorylation events
create binding sites for the dual src homology 2 (SH2) domains found in
ZAP-70, resulting in recruitment of ZAP-70 to the CD3-TCR complex. The
ITAM-bound ZAP-70 undergoes full catalytic activation on Lck-mediated
phosphorylation of the tyrosine 493 residue in the activation loop of
the ZAP-70 catalytic domain [13
]. Studies with T-cell
lines deficient in either Lck or ZAP-70, together with genetically
modified mice lacking these tyrosine kinases, have vividly illustrated
the critical role that both of these kinases play in CD3-TCR signaling
and T-cell development [14
15
16
17
]. In addition to its
kinase activity, ZAP-70 contains several tyrosine residues within the
interdomain B region located between the carboxy-terminal SH2 domain
and the kinase domain that can mediate interactions between ZAP-70 and
other intracellular signaling proteins, such as the adapter protein
p120Cbl and the guanine nucleotide exchange factor Vav
[18
, 19
]. Thus, in addition to its kinase
activity, ZAP-70 may function during CD3-TCR signaling to nucleate the
formation of protein-protein complexes critical to subsequent
generation of intracellular signals.
Two well-characterized ZAP-70 substrates are the adapter proteins LAT
(linker for activation of T cells) [20
] and SLP-76
(SH2-containing leukocyte protein of 76 kDa) [21
]. These
proteins lack intrinsic enzymatic activity but contain an array of
binding sites capable of mediating protein-protein interactions and
thereby result in the formation of critical signaling intermediates
[22
]. Consequently, ZAP-70-mediated tyrosine
phosphorylation of LAT and SLP-76 results in the inducible interaction
of these proteins with other intracellular signaling proteins,
including phospholipase C-
1 (PLC-1), Vav, and the adapter
proteins Nck, Grb2, GRAP, and Gads [22
]. Although LAT is
a transmembrane adapter protein and thus is constitutively localized to
the T-cell plasma membrane, SLP-76 is specifically recruited to the
membrane after CD3-TCR stimulation [23
]. Loss of
expression of either LAT or SLP-76 in mice results in profound defects
in T-cell development [24
25
26
], establishing the
critical role of these proteins in CD3-TCR signaling.
A third family of tyrosine kinases that is activated subsequent to
activation of src family kinases and ZAP-70 is the Tec family of
tyrosine kinases [27
]. T cells express three members of
this family, Tec, Itk, and Rlk. Structurally, Tec and Itk both consist
of a pleckstrin homology (PH) domain, a Tec homology domain, SH3 and
SH2 domains, and a kinase domain. Rlk has a similar structure, except
that it lacks a PH domain. Tec family kinases have been implicated in
PLC-1 activation, calcium flux, and mitogen-activated protein (MAP)
kinase activation [28
29
30
]. The effects of Itk on
PLC-1 activity in particular may be related to reported associations
of Itk with both LAT and SLP-76 [31
32
33
]. In B cells,
the Tec family kinase Btk is critical for B-cell development, and loss
of Btk expression results in B-cell immunodeficiency
[34
]. Studies with knockout mice suggest some redundancy
in Tec family tyrosine kinase function in T cells [30
],
although unique roles for these kinases are also emerging. For example,
Itk has been specifically implicated in the development of T-helper 2
(Th2) T cells [35
].
Itk tyrosine kinase activity requires two upstream regulatory events:
membrane recruitment of the kinase and src kinase-mediated tyrosine
phosphorylation of Itk, most likely by Lck [36
,
37
]. Membrane recruitment of Itk is dependent on the
activation of phosphatidylinositol 3-kinase (PI 3-K), a lipid kinase
that phosphorylates phosphatidylinositols at the D-3 position. The
lipid products produced by active PI 3-K at the plasma membrane can be
bound by many but not all PH domains [38
,
39
]. In the case of Itk, membrane recruitment of Itk is
dependent on the PH domain of Itk, and the Itk PH domain can bind
specifically to phosphatidyl inositol (3,4,5)-triphosphate
(PI(3,4,5)-P3). Therefore, PI 3-K, together with Lck,
coordinately regulates Itk tyrosine kinase activity. Although CD3-TCR
signaling clearly leads to activation of PI 3-K [40
,
41
], both enhancing and inhibitory effects of PI 3-K
inhibitors, such as wortmannin and LY294,002, on CD3-TCR-mediated
transcriptional activity have been reported [42
43
44
45
].
Furthermore, the mechanism by which the CD3-TCR is coupled to PI 3-K is
not clear, although CD3-TCR stimulation can enhance the association of
the p85 subunit of PI 3-K with the CD3-
subunit [46
]
and with tyrosine-phosphorylated LAT [20
]. Studies in B
cells also suggest that B-cell receptor-mediated activation of PI 3-K
is dependent on Syk tyrosine kinase activity [47
,
48
].
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TOPABSTRACTINTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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[53
], ZAP-70 [54
],
the p85 subunit of PI 3-K [55
], Vav [55
],
and SLP-76 [23
]. Clustering of microdomains with cholera
toxin B subunit or with antibodies specific for GPI-linked receptors
can initiate signaling events similar to those observed with CD3-TCR
signaling [54
], and disruption of microdomains by
depletion or sequestration of cholesterol can inhibit proximal CD3-TCR
signaling events [55
, 56
]. These studies
suggest that promotion of the colocalization of key signaling
intermediates via clustering of membrane microdomains is a key step in
productive CD3-TCR signaling.
CD3-TCR signaling to ß1 integrins
As described above, there has been extensive analysis of the
signaling events that occur subsequent to CD3-TCR ligation and have an
effect on transcriptional events in the nucleus, such as IL-2 gene
induction. However, it is unclear whether there are differences in the
signaling events that regulate one effector response downstream of
CD3-TCR stimulation, such as transcriptional activation of the
interleukin-2 (IL-2) gene, versus another, such as activation of ß1
integrin-mediated adhesion. Clearly, these effector responses are
different in several respects, including the rapidity of the response
(minutes for ß1 integrin activation vs. hours for gene induction) and
the requirement for de novo protein synthesis. Recent studies of
activation-dependent regulation of ß1 integrin function suggest in
fact that analysis of the intracellular signaling events that mediate
distinct T-cell effector responses may reveal novel insights into
CD3-TCR signaling in general.
Studies with the Lck-deficient Jurkat T-cell variant J.CaM1 [14 , 57 ] indicate that Lck is required for CD3-TCR-mediated activation of ß1 integrin function [58 ]. Although CD3-TCR stimulation fails to enhance ß1 integrin-mediated adhesion of J.CaM1 cells to fibronectin, re-expression of wild-type Lck restores this response [58 ]. A similar strategy was used with the ZAP-70-deficient Jurkat variant P116 [15 ] to demonstrate a critical role for ZAP-70 in CD3-TCR signaling to ß1 integrins [59 ]. These studies demonstrated that the kinase activity of ZAP-70 was required, because expression of a wild-type form of ZAP-70 in P116 T cells, but not a kinase-inactive form of ZAP-70, restored CD3-TCR-mediated activation of ß1 integrin function. In normal peripheral T cells, expression of kinase-inactive ZAP-70 blocked CD3-TCR signaling to ß1 integrins, providing further evidence for a role for ZAP-70 in regulating ß1 integrin-mediated adhesion. Although ZAP-70 also appears to be involved in LFA-1-dependent signaling events that regulate LFA-1-dependent migration independently of the CD3-TCR [60 , 61 ], it is currently unclear whether ß1 integrin signaling also involves CD3-TCR-independent activation of ZAP-70.
However, further studies using the P116 T-cell system have suggested possible differences in the way in which ZAP-70 regulates ß1 integrin function versus other responses downstream of TCR signaling. For example, mutation of tyrosine residue 319 in the interdomain B region of ZAP-70 to a phenylalanine (Y319F) blocks CD3-TCR-mediated activation of a nuclear factor of activated cells (NF-AT) reporter gene construct, calcium influx, Ras activation, and tyrosine phosphorylation of LAT [59 , 62 ]. However, expression of the Y319F ZAP-70 mutant in P116 T cells fully restores CD3-TCR-mediated increases in ß1 integrin-mediated adhesion to fibronectin [59 ]. These results also suggest that CD3-TCR signaling to ß1 integrins may not require calcium influx or Ras activation.
Although the kinase activity of ZAP-70 is clearly required for CD3-TCR-mediated increases in ß1 integrin function, the role of two well-characterized ZAP-70 substrates, the adapter proteins LAT and SLP-76, in regulating ß1 integrin function is not well established. In fact, several lines of evidence suggest that these two adapter proteins do not play a significant role in CD3-TCR signaling to ß1 integrins. First, as mentioned above, the Y319F mutation in ZAP-70 inhibits CD3-TCR-mediated tyrosine phosphorylation of LAT but does not affect CD3-TCR-mediated activation of ß1 integrins [59 , 62 ]. Second, expression in Jurkat T cells of a mutant form of LAT with tyrosine-to-phenylalanine mutations at residues 171 and 191 blocks CD3-TCR-mediated activation of NF-AT, but it has no effect on CD3-TCR signaling to ß1 integrins [59 ]. Third, over-expression of wild-type SLP-76 enhances CD3-TCR-mediated activation of NF-AT but does not affect CD3-TCR-mediated increases in ß1 integrin function [59 ]. Although additional studies are clearly warranted, these studies currently suggest that ZAP-70 does not mediate its effects on CD3-TCR signaling to ß1 integrins via tyrosine phosphorylation of LAT and/or SLP-76.
In B cells, there is evidence that B-cell-receptor-mediated activation of PI 3-K requires Syk activation [47 , 48 ]. Thus, it is intriguing to speculate that ZAP-70 may also be required for CD3-TCR-mediated activation of PI 3-K. This is a significant issue with regard to our understanding of CD3-TCR signaling to ß1 integrins, because inhibition of PI 3-K activity clearly blocks increases in ß1 integrin function mediated by activation of the CD3-TCR [63 ], as well as the T-cell coreceptors CD2 [64 ], CD7 [65 ], and CD28 [9 ]. Other groups have also reported a key role for PI 3-K in the activation of integrin function by other cell surface receptors, including growth factor receptors [66 67 68 ] and chemokine receptors [11 ], suggesting a common, critical function for PI 3-K in the regulation of integrin function.
Together, these studies suggest that CD3-TCR-mediated increases in ß1 integrin function require the coordinated activation of Lck, ZAP-70, and PI 3-K. Since all three of these kinases have been implicated in the activation of the Tec family tyrosine kinase Itk [36 , 37 , 69 ], we recently analyzed whether Itk might mediate CD3-TCR signaling to ß1 integrins [58 ]. This work suggests that CD3-TCR-mediated increases in ß1 integrin function require Lck- and PI 3-K-dependent activation of Itk. Expression of kinase-inactive Itk inhibits CD3-TCR activation-induced increases in ß1 integrin-mediated adhesion of both Jurkat T cells and normal human peripheral T cells [58 ]. Furthermore, CD3-TCR-mediated activation of ß1 integrin function appears to require specific targeting of Itk to membrane microdomains, because (1) CD3-TCR-mediated recruitment of Itk to membrane microdomains requires the PH domain of Itk, and (2) overexpression of the PH domain of Itk inhibits CD3-TCR signaling to ß1 integrins. CD3-TCR-dependent recruitment of Itk to membrane microdomains requires PI 3-K activity, because PI 3-K inhibitors block Itk membrane recruitment and the PH domain of Itk binds specifically to PI(3,4,5)-P3. Thus, these studies suggest that one prominent function of PI 3-K in CD3-TCR signaling to ß1 integrins is to mediate the recruitment of Itk to membrane microdomains.
Since Lck is preferentially localized to membrane microdomains, CD3-TCR stimulation likely enhances the association of Itk with Lck. Since Lck regulates Itk kinase activity [36 , 37 ], this suggests that Lck might serve to regulate CD3-TCR signaling to ß1 integrins via regulation of the kinase activity of Itk localized to membrane microdomains. Studies in COS cells are consistent with this regulatory function for Lck in Itk-mediated signaling [37 ]. In T cells, replacement of the PH domain of Itk with a farnesylation sequence results in constitutive membrane localization of this Itk construct [58 ]. However, expression of membrane-targeted Itk is insufficient by itself to result in increased ß1 integrin activity. In contrast, increased ß1 integrin function is observed upon CD4 stimulation of Jurkat T cells expressing membrane-targeted Itk [58 ]. This effect of CD4 signaling on ß1 integrin function does not occur in J.CaM1 cells, suggesting that CD4-mediated activation of Lck can, together with membrane-targeting of Itk, enhance ß1 integrin function independently of direct stimulation of the CD3-TCR complex. CD4 stimulation, together with expression of a constitutively active form of PI 3-K, can also enhance ß1 integrin function in a manner that is dependent on the kinase activity of Itk [58 ]. This result is consistent with PI 3-K serving to regulate membrane recruitment of Itk.
Thus, these studies suggest that CD3-TCR signaling to ß1 integrins requires both PI 3-K-dependent recruitment of Itk to membrane microdomains and Lck-dependent activation of microdomain-localized Itk (Fig. 1 ). Since microdomain localization of Itk or activation of Lck is not sufficient to induce increased ß1 integrin function, this suggests that Lck and PI 3-K play critical, complementary roles in the activation of ß1 integrin function by the CD3-TCR complex. It is interesting that clustering of microdomains with the cholera toxin B subunit, which can initiate proximal CD3-TCR signaling events [54 ], can also induce lymphocyte function-associated antigen-1 (LFA-1) clustering and enhance LFA-1-dependent adhesion in a wortmannin-sensitive manner [70 ]. The role of ZAP-70 in this signaling cascade remains to be elucidated, although studies of Syk function in B cells suggest that ZAP-70 might be capable of regulating PI 3-K activity in T cells. This would suggest that ZAP-70 might serve to regulate CD3-TCR-mediated recruitment of Itk to membrane microdomains. However, an analysis of Itk function in ZAP-70-deficient Jurkat T cells suggests that, although ZAP-70 does in fact play a role in regulating Itk activity, it may not do so via the regulation of membrane recruitment of Itk [69 ]. Currently, there is some discrepancy in the effects of CD3-TCR stimulation on membrane localization of Itk in Jurkat T cells that may be related to the use of different Jurkat subclones and variants [58 , 69 , 71 , 72 ]. In addition, the lack of expression of the PTEN phosphatase in Jurkat T cells may also impact on the basal levels of Itk found at the membrane and in microdomains of Jurkat T cells [71 , 73 ]. However, kinase-inactive Itk is able to inhibit CD3-TCR signaling to ß1 integrins in both PTEN-negative Jurkat T cells and PTEN-positive human peripheral T-cell blasts [58 ]. Nevertheless, these concerns highlight the need to continue to explore the role of Itk in the regulation of ß1 integrin function in T-cell systems other than Jurkat. Finally, as noted above, there is currently little evidence to support a role for either LAT or SLP-76 in CD3-TCR signaling to ß1 integrins [59 ]. However, both of these adapter proteins are found in membrane microdomains after CD3-TCR stimulation and can interact with Itk [31 32 33 ]. Thus, it is important that future studies continue to explore the potential role of either LAT or SLP-76 in Itk-dependent regulation of integrin activity.
 View larger version (15K): [in a new window] |
Figure 1. Proposed model of the regulation of ß1 integrin functional activity
by the CD3-TCR complex. CD3-TCR stimulation results in the activation
of Lck, resulting in tyrosine phosphorylation of ITAM motifs in the CD3
subunits of the CD3-TCR and subsequent recruitment of ZAP-70 to the
CD3-TCR. Lck phosphorylates and thus activates ZAP-70, which is
required for CD3-TCR signaling to ß1 integrins. CD3-TCR signaling
also leads to the activation of PI 3-K, which enhances the localization
of the Tec family tyrosine kinase Itk to membrane microdomains, where
it can be phosphorylated by Lck. Itk can regulate actin polymerization
and thus may enhance ß1 integrin avidity. ZAP-70 may participate in
this signaling cascade by regulating CD3-TCR-mediated activation of PI
3-K. See text for further details.
|
IIbß3 integrin expressed on platelets
[74
, 75
]. These changes in integrin
conformation result in enhanced binding of soluble ligand, and
inhibition of integrin-dependent cell adhesion by soluble ligand is
indicative of a role for integrin affinity in adhesive interactions.
Antibodies recognizing neoepitopes expressed on integrin subunits have
frequently been used as markers of high-affinity integrins, although
some of these neoepitopes do not correlate precisely with increased
ligand binding by the integrin in question [75
].
Currently, the role of affinity modulation in the activation-dependent
regulation of integrin function appears to be dependent on many
factors, including the specific integrin being studied, the cell type
in which the integrin is expressed, and the type of activation signal
being delivered to the cell. In mast cells, Fc
RI stimulation leads
to PI 3-K-dependent increases in 5ß1 integrin-dependent adhesion
to fibronectin that can be inhibited by soluble fibronectin fragments
[76
]. However, in contrast to what we have observed in T
cells [58
], constitutive activation of PI 3-K by itself
is sufficient to lead to enhanced 5ß1 integrin-mediated adhesion
of mast cells in the absence of additional stimulation
[76
]. Chemokine stimulation of mouse T cells also
results in rapid increases in LFA-1 affinity, but these changes in
LFA-1 conformation are independent of PI 3-K [11
]. In
contrast, CD3-TCR stimulation does not lead to increased LFA-1 affinity
[77
]. Although increased binding of soluble fibronectin
is detected after CD3-TCR stimulation of human peripheral T cells and
HUT78 T cells [63
, 78
], CD3-TCR stimulation
of Jurkat T cells does not lead to increased binding of soluble
fibronectin [63
]. Furthermore, CD3-TCR-mediated
increases in ß1 integrin function on peripheral human T cells could
not be inhibited by soluble ligand [63
]. Together, these
results suggest that CD3-TCR signaling to ß1 integrins does not
necessarily require changes in ß1 integrin conformation. However, it
should be noted that recent studies with chemokine signaling to LFA-1
suggest that the relative contribution of high-affinity integrins to
adhesion may be dependent on the density of immobilized ligand
[11
]. In addition to changes in integrin conformation, activation-dependent changes in integrin function can involve changes in integrin mobility that result in integrin clustering and consequently enhanced avidity [77 , 79 80 81 ]. The mechanisms by which different integrins are coupled to the cytoskeleton and how this coupling is regulated remain important areas of investigation. Calpeptin-sensitive proteases regulate LFA-1 clustering induced by CD3-TCR stimulation [82 ]. Changes in integrin clustering likely involve activation-dependent changes in the actin cytoskeleton, and several recent reviews have highlighted the importance of actin polymerization to T-cell function [83 , 84 ]. CD3-TCR stimulation leads to rapid polymerization of the actin cytoskeleton via activation of Rho family GTPases by guanine nucleotide exchange factors, such as Vav, and downstream activation of molecules such as Wiskott-Aldrich syndrome protein (WASP), which is involved in actin nucleation via interactions with WASP-interacting protein (WIP) and the actin-related protein (Arp2/3) complex [83 , 84 ]. Adapter proteins such as SLP-76 have been proposed to serve as key links between the CD3-TCR complex and the actin cytoskeletal machinery [85 ]. It is interesting that several studies suggest that activation-dependent regulation of integrin function in T cells may involve PI 3-K-dependent regulation of the cytoskeleton. First, chemokine stimulation of mouse T cells leads to LFA-1 clustering that is sensitive to PI 3-K inhibitors [11 ]. Second, PI 3-K inhibitors block CD3-TCR-mediated increases in human T-cell adhesion to fibronectin but do not inhibit CD3-TCR-induced changes in binding of soluble fibronectin [63 ]. Third, integrin functional activity can be regulated by exogenous expression of dominant-negative or constitutively active forms of several different guanosine triphosphate (GTP)-ases, including H-ras, R-ras, Rac, and Rap1 [86 87 88 89 90 91 92 93 ]. However, it should be noted that it is still unclear whether any or all of these GTPases are required for CD3-TCR-mediated increases in ß1 integrin function. Finally, PI 3-K can regulate LFA-1 activity via membrane recruitment of cytohesin-1, a protein that interacts with LFA-1 and also acts as a guanine-nucleotide exchange factor for ADP ribosylation factor GTPases [94 ].
There is also growing evidence that Tec family kinases may play a key
role in regulating the actin cytoskeleton. Expression of
kinase-inactive Itk or the PH domain of Itk, both of which block
CD3-TCR-mediated increases in ß1 integrin function, also inhibit
CD3-TCR-mediated actin polymerization [58
]. Itk
associates with WASP [95
], and the PH domain of Btk
interacts with F-actin [96
]. Btk has also been proposed
to regulate Rho GTPase activity in B cells [97
]. Since
phorbol ester stimulation also leads to increased integrin-mediated
adhesion [4
5
6
], recent reports of Syk- and
Btk-dependent regulation of PKC ßI upon FcRI stimulation suggest a
potential role for Tec kinases in regulating integrin function via PKC
[98
]. Finally, the lone Tec family tyrosine kinase in
Drosophila, Tec29, may regulate actin filament
reorganization at the ring canals, which are critical for oocyte
maturation [99
].
|
TOPABSTRACTINTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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Received January 3, 2001; revised March 18, 2001; accepted March 19, 2001.
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TOPABSTRACTINTRODUCTIONCURRENT CONCEPTS IN CD3-TCR...PLASMA MEMBRANE MICRODOMAINS AND...SUMMARYREFERENCES |
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1 in human T lymphocytes J. Immunol. 163,6435-6441 subunit of the T cell antigen receptor mediates enhanced association with phosphatidylinositol 3-kinase in Jurkat T cells J. Biol. Chem. 272,25310-25318 chain to glycolipid-enriched membrane domains upon T cell activation Int. Immunol. 11,1395-1401-associated protein-70 (ZAP-70) tyrosine kinase: relevance for invasion and migration of a T cell hybridoma J. Immunol. 163,4253-42611 and Ras activation EMBO J 18,1832-1844[Medline]1 pathways Blood 86,2086-2090Mß2 by LPS and other inflammatory mediators Curr. Biol. 10,974-978[Medline]This article has been cited by other articles:
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A. Sakakibara, S. Hattori, S. Nakamura, and T. Katagiri A Novel Hematopoietic Adaptor Protein, Chat-H, Positively Regulates T Cell Receptor-mediated Interleukin-2 Production by Jurkat Cells J. Biol. Chem., February 14, 2003; 278(8): 6012 - 6017. [Abstract] [Full Text] [PDF]
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Z. Li, M. J. Calzada, J. M. Sipes, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Interactions of thrombospondins with {alpha}4{beta}1 integrin and CD47 differentially modulate T cell behavior J. Cell Biol., April 29, 2002; 157(3): 509 - 519. [Abstract] [Full Text] [PDF]
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