Department of Pathology and Laboratory Medicine, Johnson Comprehensive Cancer Center, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095 USA
Accepted on June 25, 2002;
Abstract
Control of cell death is critical in eukaryotic development, immune system homeostasis, and control of tumorigenesis. The galectin family of lectins is implicated in all of these processes. Other families of molecules function as death receptors or death effectors, but galectins are uniquely capable of acting both extracellularly and intracellularly to control cell death. Extracellularly, galectins cross-link glycan ligands to transduce signals that lead directly to death or that influence other signals regulating cell fate. Intracellular expression of galectins can modulate other signals controlling cell viability. Individual galectins can act on multiple cell types, and multiple galectins can act on the same cell. Understanding how galectins regulate cell viability and function will broaden our knowledge of the roles of galectins in basic biological processes and facilitate development of therapeutic applications for galectins in autoimmunity, transplant-related disease, and cancer.
Key words: apoptosis/galectin/glycosyltransferase/immune system/T cell
Apoptosis: a matter of life and death for multicellular organisms
Programmed cell death, or apoptosis, is indispensable for proper development of multicellular organisms. Cell death shapes the proliferating mass of cells into tissues and shapes tissues into organs (Meier et al., 2000). In the mature organism, cell death plays a critical role in regulating tissue homeostasis. Dysregulation of cell death can cause disease; excess cell death is associated with immunodeficiency and neurodegenerative disorders; and diminished cell death is associated with autoimmunity and cancer (Thompson, 1995
).
To maintain the critical balance between cell proliferation and cell death, distinct families of proteins that regulate cell death have evolved. These include death-inducing ligands, death receptors, and intracellular regulators of death pathways. To date, only two families of proteins have been described as death-inducing ligands: the tumor necrosis factor (TNF) family of proteins and the galectin family (Zimmermann and Green, 2001; Rabinovich et al., 2002b
). TNF ligands bind to cognate TNF receptor polypeptides to initiate cell death. In contrast, proapoptotic galectins bind to specific saccharide ligands on cell surface glycoproteins and/or glycolipids to initiate cell death. Inside the cell, additional families of proteins promote or prevent death initiated by extracellular death ligands and receptors. The Bcl family of proteins is the best characterized family of intracellular death regulators, and it contains numerous pro- and anti-death members (Hengartner, 2000
). Similar to the Bcl family of proteins, galectins also function intracellularly to promote cell survival or cell death (Yang et al., 1996
; Kuwabara et al., 2002
). Galectins are unique among molecules regulating cell viability because they act both outside the cell to initiate death signals and inside the cell to regulate susceptibility to death.
Galectins: old dogs learning new tricks?
The galectins are an ancient family of carbohydrate binding proteins found in multicellular organisms from fungi to mammals (Cooper and Barondes, 1999; Muller, 2001
). Galectin family members are defined by a conserved carbohydrate recognition domain (CRD) with a canonical amino acid sequence and an affinity for ß-galactosides (Barondes et al., 1994
). Fourteen galectins have been identified in mammals, and some organisms such as Caenorhabditis elegans may have many more (Cooper and Barondes, 1999
; Rabinovich et al., 2002a
). The evolutionary conservation of galectins likely reflects the roles of galectins in cellular processes essential for the development and function of multicellular organisms, including cell adhesion, migration, differentiation, proliferation, and death (Cooper and Barondes, 1999
; Perillo et al., 1998
; Leffler, 2001
; Goldring et al., 2002
).
The carbohydrate binding activity of galectins is essential for many of the familys functions. Galectins can be divided into three groups based on structure: monovalent galectins containing a single CRD that may form homodimers to become functionally bivalent, bivalent tandem repeat galectins possessing two CRDs, and chimeric galectins with a single CRD and unique amino terminus (Rabinovich et al., 2002b). The multivalent nature of galectins facilitates glycan cross-linking believed to be essential in initiating cell signals, including signals leading to death (Bourne et al., 1994
; Gupta et al., 1996
; Perillo et al., 1995
; Leffler, 2001
). The basic ligand recognized by the conserved CRD is N-acetyllactosamine (LacNAc), Galß1,4GlcNAc, or Galß1,3GlcNAc, found on the termini of Asn N-linked and Ser/Thr O-linked oligosaccharides on numerous glycoproteins. However, various galectin family members bind to modified LacNAc ligands with distinct affinities (Leffler and Barondes, 1986
). Differing affinities for more complex saccharides may result in part from structural differences in the CRDs among family members (Rini and Lobsanov, 1999
).
The biological significance of specific carbohydrate ligand recognition by various galectin family members is not completely understood but may in part explain the preference of individual galectins for different glycoprotein counterreceptors. For example, both galectin-1 (gal-1) and galectin-3 (gal-3) bind to the lysosomal associated membrane proteins, laminin, and the CD3/T cell receptor (TCR) complex (Pace et al., 1999; Demetriou et al., 2001
; Hughes, 2001
). However, gal-1 specifically recognizes CD2, CD4, CD7, CD43, and CD45, whereas gal-3 binds to IgE, Fc receptors, CD66, and CD98 (Pace et al., 1999
; Walzel et al., 2000
; Hughes, 2001
). The two CRDs of gal-4 have different preferences for carbohydrate ligands, suggesting that bivalent galectins may cross-link different ligands (Oda et al., 1993
). Recognition of unique glycan ligands probably allows different galectins to exert distinct biological effects in various tissues.
Numerous galectins influence cell fate decisions (Table I). Gal-1, -7, -8, -9, and -12 are all proapoptotic (Table II). Some proapototic galectins, such as gal-1 and gal-9, directly initiate death by cross-linking cell surface receptors, whereas intracellular expression of other galectins, such as gal-7, potentiates other death signals. Interestingly, gal-3 is the only chimeric galectin identified in mammals, and is also the only antiapoptotic family member (Table I).
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A necessary end: galectins trigger T cell death
Cell death is critical for proper T cell development in the thymus. Over 90% of developing T cells (thymocytes) die in the thymus while learning to distinguish self from nonself. Thymocytes die because the cells either fail to rearrange a functional antigen receptor (failure of positive selection/nonselection) or rearrange an antigen receptor that is self-reactive (negative selection) (Kishimoto and Sprent, 2000). Therefore cell death prevents the production of nonfunctional and autoreactive T cells. These selection events occur primarily among immature CD4/CD8 double-positive thymocytes in the cortex (Kishimoto and Sprent, 2000
). Both gal-1 and gal-9 are expressed by thymic epithelial cells in the cortex that mediate thymic selection events, and both gal-1 and gal-9 kill thymocytes (Baum et al., 1995
; Perillo et al., 1997
; Wada et al., 1997
). Double-positive cortical thymocytes are the thymocyte subset most susceptible to gal-1 induced death (Figure 1) (Perillo et al., 1997
; Vespa et al., 1999
). Gal-1 and gal-9 may therefore participate in selection events critical for the development of a functional and self-tolerant T cell repertoire.
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Living in a dangerous world: regulating galectin-induced cell death
How do cells survive when they are constantly surrounded by galectins? Susceptibilty to galectins is controlled by the cell and may be regulated at three levels: (1) synthesis and modification of glycan ligands by glycosyltransferases, (2) presentation of glycan ligands by specific glycoprotein counterreceptors, and (3) intracellular signaling pathways initiated by galectin binding to glycoprotein counterreceptors.
Synthesis and modification of glycan ligands by glycosyltransferases
Gal-1 binds to the basic ligand LacNAc, as discussed, but binds with greater avidity to glycan ligands containing multiple LacNAc units (Leffler and Barondes, 1986; Merkle and Cummings, 1988
; Solomon et al., 1991
). Multiple LacNAcs may be presented on the branches of N-glycans or occur as polyN-acetyllactosamine (polyLacNAc) chains on either N- or O-linked glycans (Figure 2). Generation of polyLacNAc sequences is regulated in part by the family of core 2 ß-1,6-N-acetylglucosaminyltransferase (C2GnT) branching enzymes for O-glycans and ß-1,6-N-acetylglucosaminyltransferase V (GNTV) branching enzyme for N-glycans (Figure 2A,B) (Cummings and Kornfeld, 1984
; Yousefi et al., 1991
; Bierhuizen et al., 1994
). Regulated expression of glycosyltransferases during development and activation, creating polyLacNAc ligands, may therefore determine cell susceptibilty to gal-1 in vivo.
|
It remains to be determined whether GNTV has a similar role in regulating gal-1 death. In contrast to C2GnT, GNTV and its corresponding saccharide structure are expressed throughout thymic development (data not shown) (Figure 1A). GNTV is expressed by resting peripheral T cells, but the expression and activity of GNTV are up-regulated with activation (Figure 1B) and may modify specific glycoprotein acceptor substrates (Lemaire et al., 1994; Demetriou et al., 2001
). GNTV has been shown to regulate antigen recognition by T cells, at least in part through the creation of cell surface ligands for gal-3 (Demetriou et al., 2001
). GNTV may also create ligands for gal-1, as indirectly inhibiting GNTV activity by swainsonine treatment of activated human peripheral T cells rendered the cells partially resistant to gal-1-induced death (Perillo et al., 1995
). However, GNTV is not essential for death, because a GNTV negative murine T cell line, PHAR 2.9, was susceptible to gal-1 death (Galvan et al., 2000b
). These results may reflect other differences between primary and transformed cells, leaving unresolved the role of GNTV in gal-1-induced T cell death.
T cell susceptibility to gal-1 may be additionally regulated by glycosyltransferases competing for acceptor substrates to limit carbohydrate ligand synthesis. ST3Gal I competes with C2GnT for core 1 O-glycan substrates and thus inhibits the addition of O-linked polyLacNAc ligands for gal-1 (Figure 2B) (Priatel et al., 2000; Dalziel et al., 2001
). Interestingly, a provocative inverse correlation exists between ST3Gal I expression and gal-1 susceptibility. ST3Gal I is not expressed by gal-1-susceptible immature cortical thymocytes but is expressed by gal-1-resistant mature medullary thymocytes (Figure 1A) (Gillespie et al., 1993
). Expression of other enzymes potentially competing for core 1 O-glycan substrates, such as the ST6GalNAc IV, have also been documented to increase during early T cell activation and may therefore protect T cells from gal-1 early during the immune response (Kaufmann et al., 1999
).
Glycosyltransferases may also modify LacNAc ligands to block gal-1 binding and reduce T cell susceptibility to gal-1. Although some modifications of LacNAc are permissive for gal-1 binding, addition of either sialic acid in an 2,6 linkage to galactose or of fucose to glucosamine, modifying the LacNAc ligand, can inhibit gal-1 binding (Figure 2C) (Leffler and Barondes, 1986
; Pace et al., 1999
). SA
2,6Gal sequences are expressed on mature medullary thymocytes resistant to gal-1 death but not on gal-1 susceptible immature cortical thymocytes (Figure 1A) (Baum et al., 1996
). In addition, overexpression of ST6Gal I in a gal-1-susceptible T cell line rendered it resistant to gal-1-induced death (Galvan et al., 2000a
). FucT VII activity is up-regulated on T cell activation (Figure 1B), suggesting that regulated fucosyltransferase activity may similarly control galectin binding and susceptibility to death (Lim et al., 2001
). Changes in neuraminidase activity also accompany T cell activation and may unmask glycan ligands by removing sialic acid (Galvan et al., 1998
). Thus, the making and masking of cell surface glycan ligands may control galectin binding and triggering of T cell death.
Little is known about how glycosylation may influence other gal-1 functions or the functions of other galectin family members. Individual galectin family members have different affinities for glycan ligands. For instance, gal-3 demonstrates enhanced binding to Fuc1,2[GalNAc
1,3]Galß1,4GlcNAc compared to unmodified LacNAc (Figure 2C) (Leffler and Barondes, 1986
; Sato and Hughes, 1992
). This suggests that the glycosyltransferases synthesizing these structures may regulate functions of gal-3. A systematic evaluation of the carbohydrate binding specificities of individual galectin family members and an assessment of changes in glycosyltransferase expression during the development and activation of target cells will greatly facilitate our understanding of galectin biology. These are among the goals of the Consortium for Functional Glycomics (http://glycomics.scripps.edu).
Presentation of glycan ligands by specific glycoprotein counterreceptors
As already mentioned, different galectins can discriminate among LacNAc-bearing glycoproteins on the cell surface and selectively recognize unique complements of receptor glycoproteins. For example, gal-1 binds a specific subset of T cell glycoproteins: CD2, CD3, CD4, CD7, CD43, and CD45 (Walzel et al., 2000; Pace et al., 1999
). In addition, antibodies to GM1 inhibited gal-1 binding to neuroblastoma cells, suggesting that gal-1 may also bind to GM1 or to glycoprotein receptors in close proximity to GM1 (Kopitz et al., 1998
). Different cell surface counterreceptors for gal-1 may have distinct functions in signaling the various processes mediated by gal-1.
CD7 is essential for signaling gal-1-mediated T cell death (Pace et al., 2000). Confocal microscopy has demonstrated the colocalization of CD7 with CD43, another gal-1 counterreceptor (Pace et al., 1999
). The colocalization of CD43 with CD7 suggests that these two glycoproteins may act in concert to initiate death.
Other gal-1 counterreceptors are not essential for gal-1 initiation of cell death but appear to be regulators of death. Gal-1 binds CD45, a heavily N- and O-glycosylated receptor tyrosine phosphatase (Walzel et al., 1999; Pace et al., 1999
; Fouillit et al., 2000
; Symons et al., 2000
). Early studies using two CD45 negative cell lines implied an essential role for CD45 in signaling gal-1 death (Perillo et al., 1995
; Walzel et al., 1999
). However, neither study demonstrated restored susceptibility to gal-1 after CD45 reconstitution. In contrast, a recent study found that CD45 regulation of gal-1-induced death depends on the glycosylation state of CD45 (Nguyen et al., 2001
). These studies showed CD45 can inhibit gal-1 death but is permissive for death when modified by core 2 O-glycans during T cell development and activation (see previous discussion).
Gal-1-induced T cell death does not require CD2, CD3, or CD4 (Pace et al., 2000). However these counterreceptors may be important for mediating other biological effects of gal-1 on T cells.
Intracellular signaling pathways initiated by gal-1 binding to glycoprotein counterreceptors
Gal-1 binding to T cells results in rapid redistribution of glycoprotein counterreceptors on the T cell surface (Figure 3) (Pace et al., 1999). CD7 and CD43 colocalize in clusters after gal-1 binding that are physically separate from CD3 and CD45 clusters localized to apoptotic membrane blebs (Pace et al., 1999
). Counterreceptor clustering appears to be regulated by the presence of specific glycan ligands, such as core 2 O-glycans (Nguyen et al., 2001
). These observations suggest that dimeric gal-1 cross-links multivalent counterreceptors to build a platform initiating the intracellular signals for death (Sacchettini et al., 2001
).
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As mentioned, gal-1 binds to core 2 O-glycans and clusters CD45 (Nguyen et al., 2001). CD45 has two cytoplasmic tyrosine phosphatase domains, and clustering of CD45 has been proposed to block access of these domains to phosphorylated substrates (Majeti et al., 1998
). Gal-1 binding to lymphocytes reduced CD45 tyrosine phosphatase activity (Walzel et al., 1999
; Fouillit et al., 2000
). In addition, a pharmacologic inhibitor of tyrosine phosphatase activity enhanced gal-1-induced death and rendered a CD45+ C2GnT cell line susceptible to death (Nguyen et al., 2001
). These observations suggest that CD45 tyrosine phosphatase activity can inhibit gal-1-induced death; however, when C2GNT is expressed during T cell development or following T cell activation, gal-1 can bind to core 2 O-glycans and cluster CD45, inhibiting tyrosine phosphatase activity and allowing the initiation of cell death (Figure 3B).
Additional signaling pathways can be initiated following galectin binding to different cell types. Both gal-1 and gal-3 trigger a calcium flux in T cells (Dong and Hughes, 1996; Pace et al., 2000
; Walzel et al., 2000
). Gal-1 binding to neutrophils results in increased production of reactive oxygen species (Timoshenko et al., 1997
; Almkvist et al., 2002
). Gal-1 binding to T cells resulted in increased AP-1 DNA binding activity (Rabinovich et al., 2000
). The rapid time course of gal-1-induced death makes it unlikely that de novo transcription is required for the initiation of death, but transcription may be required for other gal-1 effects (Pace et al., 1999
).
Team players: galectins influence other cell death pathways
Many galectins both potentiate and antagonize cell death pathways in a variety of cell types. Some galectins can act extracellularly to induce apoptosis in concert with other stimuli. For example, addition of exogenous gal-8 induced apoptosis of serum-starved carcinoma cells in a carbohydrate-dependent manner (Hadari et al., 2000). However, most experiments have examined the effects of expressing cDNA encoding various galectins on cellular susceptibility to apoptosis. In this case, the galectins may act intracellularly or extracellularly, depending on whether they are secreted. From these studies, considerable evidence now supports intracellular roles for several galectin family members in regulating cell death. Gal-7 expression is induced by the tumor suppressor p53 and is associated with UVB-induced death of keratinocytes (Bernerd et al., 1999
; Polyak et al., 1997
). HeLa cells transfected with gal-7 demonstrated enhanced cytochrome c release, enhanced caspase activity, and up-regulated JNK activity in response to various apoptotic stimuli (Kuwabara et al., 2002
). In adipocytes, gal-12 expression induced apoptosis, and gal-12 expression was increased during drug-induced adipocyte apoptosis (Hotta et al., 2001
).
As mentioned previously, only gal-3 has been found to protect cells from apoptosis. Gal-3 expression in Jurkat T cells inhibited apoptosis induced by Fas, staurosporine, and chemotherapeutic agents (Yang et al., 1996). Expression of gal-3 protected breast cancer cells from death induced by chemotherapeutic agents, nitric oxide, and detachment (Akahani et al., 1997
; Kim et al., 1999
; Moon et al., 2001
). Gal-3 possesses an NWGR motif characteristic of Bcl family members that is necessary for both gal-3 and Bcl-2 antiapoptotic activity (Yang et al., 1996
; Akahani et al., 1997
). The motif is believed to facilitate the interaction of Bcl family members and, because gal-3 coimmunoprecipitated with Bcl-2 from Jurkat T cells, may facilitate the association of gal-3 with Bcl proteins (Yang et al., 1996
). Phosphorylation of gal-3 at ser-6 is required for antiapoptotic activity, and dephosphorylation at ser-6 is required for carbohydrate ligand binding (Mazurek et al., 2000
; Yoshii et al., 2002
). Similar to Bcl family members, intracellular gal-3 preserved mitochondrial integrity and prevented cytochrome c release from mitochondria in breast cancer cells after challenge with staurosporine and chemotherapeutic agents (Matarresea et al., 2000
; Yu et al., 2002
). Therefore, although gal-3 can be secreted, the antiapoptotic effect appears to be mediated by intracellular gal-3 (Sato et al., 1993
). Exogenous gal-3, however, induced differentiation of a kidney epithelial cell line and proliferation of fibroblasts, demonstrating that extracellular gal-3 can also influence cell fate (Inohara et al., 1998
; Hikita et al., 2000
).
Secreted gal-3 has also been proposed to regulate TCR signaling by binding glycan ligands synthesized by GNTV (Demetriou et al., 2001). GNTV/ T cells demonstrated increased TCR clustering on stimulation and T cell hyperactivation compared to wild-type cells (Demetriou et al., 2001
). GNTV/ mice developed autoimmune kidney disease and exhibited increased susceptibility to experimental autoimmune encephalitis, a model for multiple sclerosis (Demetriou et al., 2001
). These results imply that gal-3 interacts with the TCR to raise the threshold for T cell activation by limiting TCR clustering. Recent studies have also demonstrated that gal-3 modulates interactions of developing thymocytes with thymic epithelia, suggesting that gal-3 may influence TCR signaling events during thymocyte selection (Villa-Verde et al., 2002
).
Gal-1 also influences T cell death resulting from TCR ligation (Figure 3). TCR stimulation and gal-1 treatment acted synergistically to kill T cell lines and thymocytes while inhibiting TCR-induced proliferation (Perillo et al., 1997; Vespa et al., 1999
; Chung et al., 2000
). Concomitant TCR engagement and gal-1 treatment also killed C2GNT lo CD4/CD8 single-positive thymocytes, a population normally resistant to death induced by gal-1 alone (Vespa et al., 1999
). This suggests that death induced by gal-1 alone and death induced by gal-1 and TCR stimulation may proceed via different mechanisms. Miceli and co-workers (Chung et al., 2000
) have proposed that gal-1 limits the formation of the immune synapse, a clustering of receptors and signaling molecules in membrane microdomains that is required to transduce TCR signals leading to activation and proliferation (Figure 3C).
Galectin knockouts: beginning to define functions
To investigate the roles of galectins in development and immune regulation, gal-1- and gal-3-null mice have been generated (Poirier and Robertson, 1993; Colnot et al., 1998a
). In gal-1/ mice, olfactory neurons showed altered neurite outgrowth and targeting, demonstrating a role for gal-1 in neural development (Puche et al., 1996
). No dramatic effects on immune development were observed in gal-1/ mice that were otherwise wild type. However, defects in immune homeostasis were observed in gal-3/ mice. Altered inflammatory cell dynamics during acute peritonitis indicate a role for gal-3 in leukocyte recruitment and/or maintenance (Colnot et al., 1998b
; Hsu et al., 2000
).
Results obtained from in vitro studies, such as the ability of both gal-1 and gal-9 to induce T cell apoptosis, suggest that there may be functional redundancy among galectin family members, although there is not yet clear evidence for redundancy in vivo. To examine functional redundancy in vivo and to understand clearly the roles of galectins in various biological processes, mice with mutations in multiple galectins will need to be generated. In addition, detailed analysis of specific biological questions using galectin-null mice crossed onto various genetic backgrounds may also be informative.
Galectins as immunomodulatory agents and therapeutics
What causes autoimmune disease? Self-reactive T cells that trigger autoimmune disease can arise through two mechanisms: a failure to eliminate self reactive T cells during development in the thymus or a breakdown in peripheral T cell tolerance for self-antigens (Kishimoto and Sprent, 2000). Two classes of T cells are associated with the initiation and maintenance of autoimmune disease. TH1 CD4+ cells mediate a cellular inflammatory and cytotoxic T cell response in such diseases as multiple sclerosis and Type I diabetes. TH2 CD4+ cells promote the production of autoantibodies in such diseases as systemic lupus erythematosus. Manipulating the TH1/TH2 balance can be therapeutic in many models of autoimmune disease.
Galectins have been used successfully as therapeutics in several TH1-mediated autoimmune disease models (Table II). Before the effects of gal-1 on T cells were known, gal-1 administration was used to treat animal models of myasthenia gravis and multiple sclerosis. Gal-1 treatment resulted in decreased antigen-induced T cell proliferation in both models, as well as the inability to isolate antigen-specific T cell clones from the multiple sclerosis model, suggesting that deletion or anergy of autoreactive T cells occurred in gal-1-treated animals (Levi et al., 1983; Offner et al., 1990
). In some animal models, gal-1 treatment resulted in a decrease in TH1 cytokines and an increase in TH2 cytokines (Table II), suggesting that gal-1 may preferentially suppress or delete TH1 CD4+ T cells. How does gal-1 mediate this shift in the immune response? It is unclear, but several possibilities exist. Gal-1 alters T cell receptor signaling and suppresses TH1 cytokine production, both of which can influence the further differentiation of naive CD4+ T cells into TH1 or TH2 effector cells (Leitenberg and Bottomly, 1999
; Vespa et al., 1999
; Rabinovich et al., 1999a
; Chung et al., 2000
). Alternatively, gal-1 may preferentially bind to and kill TH1 cells as TH1 and TH2 cells display different glycosylation profiles (Figure 1B). Indeed, amelioration of disease in several models correlated with increased T cell apoptosis (Table II), although effects on specific helper T cell subsets were not addressed.
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There is still much to be learned about the galectinsthe cells they affect, subtleties in glycan ligand preference, the identity of specific counterreceptors, and signaling pathways triggered by the counterreceptors. With this knowledge, various galectins may be useful immunotherapeutics for autoimmune and transplant-related disease or as specific adjuvants to bolster a specific immune response during infection, vaccination, or cancer therapy.
Acknowledgments
We apologize to the authors of publications not cited due to space limitations. The authors thank M. Carrie Miceli, Leland D. Powell, Karen Pace, and members of the Baum and D. J. Rawlings labs for critically reading the manuscript, and Jamey Marth for helpful discussion. J.D.H. is supported by NIH training grants GM08042 and CA009120. This work was supported by NIH grant GM63281 and an award from the Jonsson Comprehensive Cancer Center to L.G.B.
Abbreviations
C2GnT, core 2 ß-1,6-N-acetylglucosaminyltransferase; CRD, carbohydrate recognition domain; GNTV, ß-1,6-N-acetylglucosaminyltransferase V; polyLacNAc, polyN-acetyllactosamine; TCR, T cell receptor; TNF, tumor necrosis factor.
Footnotes
1 To whom correspondence should be addressed; E-mail: lbaum@mednet.ucla.edu
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