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Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
Correspondence: Susan K. Pierce, NIAID/NIH/Twinbrook II, 12441 Parklawn Drive, Room 200B, MSC 8180, Rockville, MD 20852. E-mail: spierce{at}nih.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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Key Words: multichain immune recognition receptors • Src family kinases • tyrosine phosphorylation • immune cell activation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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R1s) expressed by
mast cells and basophils. These receptors are each composed of
ligand-binding chains that allow recognition of soluble antigens for
the BCR, of peptide-major histocompatibility complexes (MHCs) on cell
surfaces for the TCR, and of antigen-IgE complexes for the FcR1. The
ligand-binding chains are integral membrane proteins with small
intracellular domains that have no inherent kinase activity and are
themselves inert with regard to signaling. Signaling is achieved
through the association of the ligand-binding chains with subunits that
contain in their cytoplasmic domains immunoreceptor tyrosine-based
activation motifs (ITAMs). Cross-linking, or oligomerization, of the
receptors after ligand binding results in phosphorylation of the ITAM
tyrosines by an Src family kinase, which triggers the signaling
cascade. The sequence of biochemical events that ensues after the
phosphorylation of ITAM tyrosine residues is understood in significant
detail; however, the initial event that triggers the association of the
Src family kinase with the oligomerized receptors remains to be
elucidated. A clue as to how MIRRs associate with Src family kinases after oligomerization has come from the results of cell biologists studying the mechanisms of protein sorting in polarized epithelial cells. Specialized cholesterol- and sphingolipid-rich membrane microdomains, termed "lipid rafts," have been described which appear to function as platforms for both protein trafficking and signaling [1 , 2 ]. Rafts exist as liquid-ordered microdomains due to the structural properties of sphingolipids and cholesterol that allow their tight packing and separation from the more loosely organized plasma membrane phospholipids. These rafts are envisioned to float in a sea of phospholipids, providing a mechanism for the lateral sorting of membrane components. Thus, a central feature of these rafts is their ability to selectively include or exclude membrane proteins. It is significant, in terms of immune cell signaling, that rafts have been shown to concentrate the Src family kinases [3 ]. Rafts are insoluble in nonionic detergents at low temperatures—conditions in which the phospholipid-containing membranes are soluble [1 , 2 ]. This characteristic of lipid rafts is exploited to isolate rafts from immune cells and examine their composition. Current evidence indicates that the MIRRs are excluded from lipid rafts in resting cells and thus sequestered away from the Src family kinases essential for the initiation of signaling [4 ] (Fig. 1 ). After oligomerization induced by ligand binding, MIRRs translocate into lipid rafts where the Src family kinases phosphorylate the MIRRs’ ITAMs, initiating signaling cascades. In this report, the current understanding of the function of rafts in immune cell activation is reviewed. Although evidence shows that rafts have a key role in the initiation of MIRR signaling, much remains to be learned concerning their composition and nature, the mechanism by which oligomerized MIRRs become raft associated, and the role rafts play in the initiation, prolongation, and regulation of receptor signaling. An exciting theme that emerges from the present studies is that immune cell activation is controlled by regulating the access of MIRRs to the rafts. Indeed, such access appears to be influenced by differentiation and the developmental state of cells, by coreceptors, and by viral infection. The role of rafts in the prolongation of signaling is also addressed, particularly with regard to the formation of the recently described immunological synapse [5 ].
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PROPERTIES OF LIPID RAFTS |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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Although it is possible to demonstrate that lipids exist in multiple phases in model membranes despite extensive characterization of such model membranes, it has been challenging to demonstrate that these phases exist in living cells. Nevertheless, recent evidence provides strong support for the existence of discrete liquid-ordered membrane microdomains in cells. Lipid rafts are insoluble in nonionic detergents at 4°C and consequently can be separated from phospholipid-containing membranes after detergent solubilization by buoyant density gradient centrifugation [1 , 2 ]. Based on the ratio of sphingolipids to phosphatidylcholine, it is estimated that rafts make up approximately 30% of lymphocyte membranes [11 ]. Rafts are dependent on cholesterol, and depletion of cholesterol by treatment of cells with cholesterol-depleting or -sequestering drugs before detergent extraction results in the solubilization of raft-associated proteins. Thus, proteins associated with rafts in a cholesterol-dependent fashion after detergent solubilization are assumed to have been associated with rafts in the living cell [7 ]. Using detergent insolubility to isolate rafts from unstimulated cells rafts have been shown concentrate glycosylphosphatidylinositol (GPI)-linked proteins [12 ] and proteins doubly acylated by myristoylation and palmitoylation or by double palmitoylation [1 , 2 ]. A few transmembrane proteins have been identified in rafts of resting cells, particularly ones that are palmitoylated, but the majority of plasma membrane proteins are excluded [2 ].
There are, however, significant caveats regarding the use of detergent extraction to identify raft components. The insolubility of rafts in nonionic detergents appears to arise from the tight packing of the sphingolipids and cholesterol [13 ]. The degree to which the rafts will solubilize depends on the stability of the lipid-lipid interactions versus the lipid-detergent interactions. These can depend on the lipid composition and the particular detergent used and its concentration [7 , 14 , 15 ]. For example, if the cells are incompletely solubilized, most proteins will appear in the buoyant fractions of the density gradient. Thus, demonstration of the cholesterol dependence of the detergent insolubility of a protein is essential. In addition, it is not known whether raft-associated proteins are randomly distributed in all rafts or specialized rafts concentrate subsets of raft proteins [16 , 17 ]. Thus, it is possible that not all rafts are equally soluble. Proteins might also have a range of affinities for rafts, resulting in a range of detergent solubilities. Moreover, not all raft proteins can float on sucrose gradients. For example, connection of a raft protein to the cytoskeleton, as occurs with activation of the MIRRs, might cause the protein to sediment in density gradients after detergent extraction [14 ]. It is also a concern that detergent extraction itself might induce the formation of cholesterol- and sphingolipid-rich insoluble membranes. Nevertheless, despite these potential pitfalls, when used conservatively, detergent insolubility is a valuable tool for the study of rafts.
Recent studies using advanced technologies have complemented analyses
of rafts isolated by detergent solubilization and have provided a
strong case for the existence of rafts in living cells. The first
evidence came from a demonstration that raft and nonraft proteins form
sharply separated clusters on the plasma membrane using specific
antibodies [18
]. Subsequently, fluorescence resonance
energy transfer [19
] and chemical cross-linking
[20
] were used to demonstrate that GPI-linked proteins
are present in cholesterol-dependent membrane microdomains in living
cells. In addition, liquid-ordered membrane microdomains were
identified in living cells by using single dye-tracing methods
[21
], and photonic-force microscopy [22
]
was used to demonstrate the presence of small sphingolipid-cholesterol
microdomains in living cell membranes. Last, using electron microscopy
it was possible to demonstrate the presence of rafts and FcR1s in
clustered rafts in mast cells [23
].
The analysis of rafts in living cells revealed them to be dynamic lipid-protein complexes that diffuse in the plasma membrane as single entities for minutes [22 ]. Rafts appear to be equally distributed over the cell surface and show no polarity in resting cells. Analyses of rafts in living cells provide an estimate of the size of rafts. Rafts appear small—in one study, 26 nm in diameter [22 ]; in another, 70 nm in diameter [19 ], corresponding to about 3,500 sphingolipid molecules [22 ]. The number of proteins in individual rafts is estimated at 10–30 [7 ]. Thus, rafts in resting cells are submicroscopic in size and cannot be imaged by conventional techniques. However, the cross-linking of raft-associated proteins or glycosphingolipids can result in the aggregation or coalescence of rafts into large patches, hundreds of nanometers in diameter, which can be easily viewed by fluorescence microscopy [18 , 24 ]. The aggregated rafts are referred to as clustered rafts. As described below, the clustering of rafts might be a critical step in immune cell signaling.
Thus, the evidence supports the existence of small cholesterol- and sphingolipid-rich membrane microdomains in living cells. However, there is much to be learned about the composition and biophysical nature of rafts and their formation in cell membranes.
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ROLE OF LIPID RAFTS IN IMMUNE CELL SIGNALING |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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Lipid rafts isolated from resting immune cells by detergent solubilization and density gradient centrifugation have been shown to be enriched in proteins that fall into two main categories, namely those involved in signal transduction and those that are components of the cytoskeleton [7 , 25 , 26 ]. Given that ligand binding by the MIRRs initiates signaling cascades and is accompanied by attachment of MIRRs to the actin cytoskeleton, this result is consistent with a role for rafts as signaling platforms. Table 1 summarizes the components of the MIRR signaling cascades and cytoskeletal proteins reported to be raft associated in T cells, B cells, and mast cells. In addition to these, other important immune cell plasma membrane proteins have been reported to be constitutively associated with rafts or induced to associate with rafts after cell activation. These include the MHC class II molecules [27 ] and CD20 [28 ] on B cells, CD44 [29 , 30 ] and CD48 [31 ] on T cells, and CD40 on B cells [32 ] and dendritic cells [33 ].
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Rs, are myristoylated and
palmitoylated [34
35
36
]. LAT, a transmembrane adapter
protein that plays a role in T cell activation, is dually palmitoylated
[37
]. A variety of immune cell surface proteins are
associated with rafts through GPI linkage to the membrane, including
Thy1, Fc
RIII, and LFA-3 [12
]. Although lacking
transmembrane and cytoplasmic domains, these proteins have been
demonstrated to transduce signals, and it has been proposed that the
mechanism of signaling is related to raft function. In addition to
proteins directly targeted to rafts by modification with lipids,
proteins can be associated with rafts indirectly due to their binding
to raft-associated proteins as occurs for many of the components of
signaling cascades and the cytoskeleton. The ability to isolate
proteins peripherally associated with rafts might be highly variable. The targeting of proteins to rafts appears to be selective, and the exclusion of proteins from rafts might have significant functional repercussions. For example, although the rafts concentrate the Src family kinases, the phosphatase CD45, which can function to dephosphorylate MIRRs, is excluded from rafts [38 ]. Similarly, although proteins acylated by myristoylation or palmitoylation are targeted to rafts, prenylated proteins such as H-Ras, Rab5, and Gß are excluded [39 ]. The significance of correct targeting to rafts is demonstrated by the disruption of signaling when targeting fails. For example, mutations that alter palmitoylation of LAT disrupt the association of LAT with rafts and impair signaling through the TCRs [37 ]. Presumably both the inclusion and the exclusion of membrane and cytosolic proteins from rafts reflect the overall compartmentalization of the signaling apparatus.
Significantly, after cross-linking and oligomerization the MIRRs become raft associated (Fig. 1) . Subsequently, a variety of proteins involved in signaling as well as components of the cytoskeleton are recruited to rafts [7 , 15 , 40 , 41 ]. Thus, rafts appear to function as platforms for signaling where the signaling complexes are assembled and receptors become attached to the actin cytoskeleton.
If rafts do indeed function as signaling platforms, a complete understanding of the entire protein content of the rafts is essential to gain an understanding of the mechanisms by which signaling complexes are assembled and function. The identification of raft-associated proteins to date has been primarily by immunoblotting of raft fractions by specific antibodies. Thus, the list of raft-associated proteins given in Table 1 in all likelihood represents only a partial list of the usual suspects. Recently, advances in protein identification technologies, developed as components of what is referred to as proteomics, have been applied to the identification of raft-associated proteins. One such study using microcapillary liquid chromatography electrospray ionization tandem mass spectrometry identified more than 70 different proteins in the rafts of an unstimulated T cell line [42 ]. It is striking that the majority of these proteins were either cytoskeleton proteins or proteins involved in signal transduction and included those listed in Table 1 . The further application of proteomic technologies to the identification of immune cell rafts might lend insights into the mechanisms by which MIRR signaling is initiated and regulated.
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THE MECHANISM OF MIRR RAFT ASSOCIATION |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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Rs containing the transmembrane region of raft-excluded
proteins are not induced to associate with rafts after cross-linking
[45
]. The transmembrane region of CD45 has been shown to
confer detergent solubility on the hyaluronase receptor CD44, which is
constitutively associated with rafts and is detergent insoluble
[29
]. In addition, mutations in the transmembrane domain
of the Ig chains of BCRs toward the endoplasmic leaflet alter the
temperature dependence of raft association [46
].
Clearly, an understanding of the nature of the MIRR oligomer that
confers a high affinity for rafts is of considerable importance in
understanding initiation of signaling.
The mechanism by which the oligomers of the MIRRs translocate
into rafts is also only poorly understood at present. The association
of cross-linked receptors with rafts apparently precedes any tyrosine
phosphorylation events and moreover is not dependent on the signaling
components of the receptor. Thus, raft association of the BCR and
IgR after cross-linking occurs in the presence of Src family kinase
inhibitors [46
47
48
]. In addition, a BCR mutant that does
not contain the signal-transducing subunits of the BCR associates with
rafts after cross-linking [46
]. It is significant that
the association of rafts with the actin cytoskeleton does not appear to
be a requisite of MIRR raft association. Association of the BCR and
FcR1 occurs in the presence of drugs that disassociate the actin
cytoskeleton [46
, 49
]. Thus, the binding of
multivalent ligands is the only known requirement for association of
MIRRs with rafts. This implies that the only control of MIRR raft
association is the ligand’s ability to cross-link or oligomerize
MIRRs. In this regard, the initial step in MIRR-induced immune cell
activation is a ligand-sensing event, presumably dependent only on the
affinity of ligand for the receptor and its valency.
Although the association of cross-linked receptors with rafts appears to be independent of tyrosine phosphorylation of the receptor and of attachment to the actin cytoskeleton, these are two very early steps in the signaling cascade, and receptors that fail to initiate these events in rafts might not be maintained in rafts. Thus, oligomerization of the receptor might increase its affinity for rafts, resulting in a longer yet transient residency time in rafts during which signaling can be initiated. If signaling is not initiated, the receptor might diffuse out of the rafts.
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RAFT CLUSTERING AND THE FORMATION OF THE IMMUNOLOGICAL SYNAPSE |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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The end point of ligand engagement of MIRRS, at least for T cells and B cells, appears to be the formation of the "immunological synapse." The synapses are highly ordered, polarized membrane structures in which the MIRRs, signaling components, cytoskeleton components, and cell adhesion molecules are concentrated [5 ]. For T cells, synapses form at the junctions of T cells and the antigen-presenting cells that express the peptide-MHC complexes bound by TCRs. The synapse appears to be a dynamic structure, the assembly of which can require several discrete steps. The mature synapse contains, on the surface, a central cluster of TCRs ringed by adhesion molecules and, on the cytoplasmic side, signaling molecules including the Src family kinases, protein kinase C, and the intregrin-associated cytoskeletal proteins including talin [50 51 52 ]. The synapse forms several minutes after ligand engagement at 37°C [5 , 53 , 54 ] and requires an intact cytoskeleton [52 , 55 ]; in this regard this process is distinct from MIRR raft association (Table 2 ). The synapse is a highly stable structure that persists for longer than an hour, and its maintenance correlates with full T cell activation [5 ]. One of the distinctive features of T cell activation is the small number of peptide-MHC complexes (10–100) that the TCRs need to engage [56 ]. It has been proposed that the same peptide-MHC complex is engaged repeatedly by TCRs during a period of hours to generate an adequate signal for activation. The immunological synapse might provide an opportunity for these interactions to occur. Significantly, evidence from several laboratories indicates that the association of the TCR with rafts and raft clustering are essential features of the formation of immunological synapse in T cells [4 , 15 ].
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2, and actin. Excluded were CD22,
CD45, and SHP-1 molecules involved in the negative regulation
of BCR signaling. The role of the synapse in B cell activation is not
known, although it presumably functions to allow prolonged BCR
signaling. The essential features of the association of MIRRs with rafts and the formation of the immunological synapse are summarized in Table 2 . Based on current evidence, a simple model for the association of TCRs with rafts, raft clustering, and ultimately formation of immunological synapse can be proposed. First, MIRR oligomerization leads to immediate raft association in a process that occurs at 4°C [40 , 58 ], is kinase independent [47 , 48 , 58 ], and does not require an intact cytoskeleton [46 , 49 ]. Phosphorylation of ITAMs and initiation of signaling proceed in the rafts [7 , 15 , 40 ]. Successful initiation of signaling causes clustering of the rafts and the association with the actin cytoskeleton [7 , 15 ]. The clustered rafts are then polarized in a process that requires several minutes at 37°C [5 , 53 , 54 ] and an intact cytoskeleton [52 , 55 ]. The polarized receptors are further spatially organized by mechanisms that remain to be elucidated, resulting in the immunological synapse. The mechanisms that facilitate raft clustering and association with the actin cytoskeleton are not known but might represent key points of regulation of MIRR signaling. Indeed, as suggested above, if the ligand-bound MIRRs that associate with rafts cannot become clustered and associated with the cytoskeleton, signaling might not proceed to the formation of a synapse. Although current results fit the overall temporal order of the events depicted in Figure 1 , much needs to be learned concerning the process by which ligand-engaged receptors associate in rafts, cluster, and are polarized.
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REGULATION OF THE ASSOCIATION OF MIRRS WITH RAFTS |
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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MIRR raft association during development
The generation of a mature T and B cell repertoire devoid of
self-reactive cells and capable of responding to foreign antigen
requires discrete stages of negative and positive selection during
development [59
60
61
]. For B cells, a pre-BCR is first
expressed at the pre-B cell stage, and its expression is required to
signal for further development to the immature stage. The
immunoglobulin gene is assembled from multiple gene segments in an
error prone process, and any cell that fails to produce a functional
immunoglobulin must be eliminated. Thus, pre-B cell signaling might be
ligand independent and simply require the cell surface expression of
the receptor. Significantly, the pre-BCR has been observed to be
constitutively associated with rafts suggesting that raft association
is necessary for ligand-independent signaling [62
]. It
is not known yet what properties of the pre-B cell rafts promote
pre-BCR association.
Cross-linking the BCRs in immature B cells leads to apoptosis rather than activation, and recent studies show that the BCR is excluded from rafts even after cross-linking [63 , 64 ]. Thus, signaling for apoptosis appears to occur from outside rafts. It is not known what feature of the immature B cell rafts results in exclusion of the receptor, whether there are ways in which the BCRs can be cross-linked to promote association with rafts, and whether raft association would rescue the cells from apoptosis. The BCR also appears to be excluded from rafts in tolerant B cells, in which case the cross-linking of the receptor fails to activate the cell [47 ]. Thus, control of access of the BCRs to rafts appears to be a part of the mechanism that determines the fate of BCR signaling during development and antigen-driven differentiation.
Similar phenomena have been described for the TCRs during T cell development. The pre-TCR has been observed to localize in rafts without any apparent need for ligation, resulting in phosphorylation of the TCRs [65 ]. In contrast, TCRs expressed by immature thymocytes do not become raft associated after coligation of TCRs and the coreceptor CD28—conditions that lead to raft association and cell activation in mature T cells [66 ]. Recent evidence indicates that the access of TCRs to rafts might differ in TH1 and TH2 cells, a phenomenon that might be related to the sphingolipid content of the two differentiated cell types [67 ]. Clearly, a further characterization of the composition of the rafts from both B and T cells at different developmental and differentiated stages might reveal important clues as to how the association of MIRRs with rafts is regulated during development and differentiation.
Regulation of MIRR raft association by coreceptors
In mature lymphocytes, the outcome of MIRR ligand engagement is
dramatically altered by the engagement of receptors. Recent studies in
both B and T cells suggest that coreceptors influence the association
of MIRRs with rafts. For B cells, the complex of the complement
receptor, CD21, and CD19 functions as a positive regulator of BCR
signaling [68
]. The CD19-CD21 complex is coligated to
the BCRs by the binding of complement-tagged antigens and serves to
reduce the threshold for B cell activation. In resting B cells, the
CD19-CD21 complex resides outside of lipid rafts. The coligation of the
CD19-CD21 complex and BCRs by binding complement-tagged antigens causes
the association with rafts of BCRs and the CD19-CD21 complex
[69
]. The association of BCRs and the CD19-CD21 complex
with the rafts is considerably prolonged (for more than an hour) as
compared with BCR cross-linking alone. Thus, the CD19-CD21 complex can
prolong BCR residency in the rafts, possibly by prolonging raft
clustering. In contrast, the FcRIIs expressed by B cells function as
negative regulators of B cell signaling when coligated to the BCRs by
the binding of immune complexes [70
]. Recent results in
our laboratory indicate that FcRIIs are excluded from rafts in
resting cells but, when coligated to the BCRs, associate with rafts
along with the BCRs (S.-J. Tzeng, unpublished results). The FcRIIs
cause the destabilization of the BCRs in rafts and their rapid
dissociation from rafts. This effect of the FcRIIs on the BCRs might
be related to recruitment of the phosphatase SHIP-1 to the
rafts. Thus, a common feature of the B cell coreceptors might be their
ability to influence the stability of BCRs in rafts. The effect of
coreceptors on the clustering of rafts or on synapse formation has not
been directly investigated.
For T cells the engagement of the coreceptors CD48 [31 ] and CD28 [71 ] has been shown to enhance the recruitment of rafts to the immunological synapse, resulting in enhanced T cell signaling. Recently, galectin-1, a lectin expressed by activated T cells that when engaged antagonizes TCR signaling, has been shown to prevent CD48- and CD28-induced recruitment of rafts to the synapse [72 ]. It was suggested that galectin-1 might exert its effect by blocking raft clustering by inappropriately cross-linking raft components. Thus, for both T and B cells, coreceptors appear to function, at least in part, by influencing the association of MIRRs with rafts or the clustering of rafts. Coreceptors that enhance receptor signaling promote raft association, and coreceptors that dampen receptor signaling destabilize MIRR raft association. Molecular events that are influenced by coreceptors have not been fully elucidated and are of considerable interest.
Pathogens and raft function
If rafts play a central role in immune cell signaling, it is not
surprising that pathogens might co-opt rafts to propagate and influence
immune responses directed toward the pathogen. There are several
examples of pathogenic viruses, bacteria, and parasites that use rafts
to infect cells, for intracellular survival, and for budding from cells
[10
]. In addition, bacterial toxins have been shown to
bind to components of rafts for the purpose of concentrating, entering,
and inducing signaling in target cells. Gene products of the
Epstein-Barr virus, latent membrane protein (LMP)1 and LMP2A,
have been show to be constitutively present in rafts and to influence B
cell signaling [43
, 73
74
75
]. LMP1 functions
in a manner similar to ligand-bound CD40 in activating B cells, and
LMP2A mimics the functions of the activated BCRs in rafts. The virus
might be co-opting B cell signaling receptor functions to create an
intracellular environment conducive for propagation and to block B cell
responses. It is likely that there are additional examples of viruses
that influence immune cell function by pirating raft function. An
understanding of the means by which the viral proteins function in
rafts is likely to shed light on basic mechanisms of immune cell
function.
In summary, recent studies have shown that the initiation and prolongation of signaling in immune cells require the spatial organization of the MIRRs on plasma membrane. After ligand binding, MIRRs appear to first segregate into lipid rafts and ultimately form highly ordered, polarized immunological synapses. The segregation serves to concentrate signaling and cytoskeletal components required for full activation and exclude negative regulators of MIRR function. Significantly, the spatial organization can be disrupted or stabilized by a variety of factors that control MIRR signaling; thus, the segregation of MIRRs on the plasma membrane appears to be a key point of regulation. A more complete understanding of how the spatial organization of MIRRs is achieved might lend insight into ways in which this organization can be manipulated to turn immune cell responses on and off.
Received July 26, 2001; revised August 11, 2001; accepted August 14, 2001.
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TOPABSTRACTINTRODUCTIONPROPERTIES OF LIPID RAFTSROLE OF LIPID RAFTS...THE MECHANISM OF MIRR...RAFT CLUSTERING AND THE...REGULATION OF THE ASSOCIATION...REFERENCES |
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B factor kinase (IKK) complex plays a role in the activation of the NF-B cascade by TCR and CD28 J. Immunol. 165,6933-6940This article has been cited by other articles:
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