Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death

Cabrera, Paula; Amano, Maho; Mitoma, Junya; Chan, Jessica; Said, Jonathan; Fukuda, Minoru; Baum, Linda G.

doi:10.1182/blood-2006-04-018556

Cited by 45 publications

(41 citation statements)

References 57 publications

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“…1B). However, in contrast to what we have observed for galectin-1 T cell death (9,10,40), expression of the core 2 ␤-1,6-N-acetylglucosaminyltransferase (C2GnT) was not essential for galectin-9-induced death, as BW5147 T cells that lack C2GnT expression were susceptible to galectin-9-induced cell death, whereas the cells were resistant to galectin-1 (Fig. 1B).…”

Section: Galectin-9-induced T Cell Death Requires Different Glycan LIcontrasting

confidence: 50%

“…1B). We also examined the human HH T cell line, which, like BW5147 cells, has reduced cell surface core 2 O-glycans and is resistant to galectin-1 (40), and found that HH cells were also susceptible to galectin-9 (data not shown). Thus, unlike galectin-1, galectin-9-induced cell death does not require expression of core 2 O-glycans on cell surface glycoprotein receptors.…”

Section: Galectin-9-induced T Cell Death Requires Different Glycan LImentioning

confidence: 99%

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Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

Earl

Jacobs

et al. 2008

Journal of Biological Chemistry

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135

117

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The galectin family of lectins regulates multiple biologic functions, such as development, inflammation, immunity, and cancer. One common function of several galectins is the ability to trigger T cell death. However, differences among the death pathways triggered by various galectins with regard to glycoprotein receptors, intracellular death pathways, and target cell specificity are not well understood. Specifically, galectin-9 and galectin-1 both kill thymocytes, peripheral T cells, and T cell lines; however, we have found that galectin-9 and galectin-1 require different glycan ligands and glycoprotein receptors to trigger T cell death. The two galectins also utilize different intracellular death pathways, as galectin-9, but not galectin-1, T cell death was blocked by intracellular Bcl-2, whereas galectin-1, but not galectin-9, T cell death was blocked by intracellular galectin-3. Target cell susceptibility also differed between the two galectins, as galectin-9 and galectin-1 killed different subsets of murine thymocytes. To define structural features responsible for distinct activities of the tandem repeat galectin-9 and dimeric galectin-1, we created a series of bivalent constructs with galectin-9 and galectin-1 carbohydrate recognition domains connected by different peptide linkers. We found that the N-terminal carbohydrate recognition domain and linker peptide contributed to the potency of these constructs. However, we found that the C-terminal carbohydrate recognition domain was the primary determinant of receptor recognition, death pathway signaling, and target cell susceptibility. Thus, carbohydrate recognition domain specificity, presentation, and valency make distinct contributions to the specific effects of different galectins in initiating T cell death.Cell death is an essential factor in T cell development, which regulates selection of functional T cells during development in the thymus, as well as elimination of activated T cells after microbial infection or other exposure to antigen (1, 2). A number of distinct T cell death pathways have been described, including those triggered by members of the galectin family of vertebrate lectins (3-5). Galectin-1 was the first family member described to induce death of developing thymocytes and activated peripheral T cells, and the galectin-1 T cell death pathway is the best characterized to date. Specific glycoprotein receptors involved in galectin-1 death and specific types of O-and N-glycan ligands required for galectin-1 death have been identified, and galectin-1 has been shown to trigger a novel intracellular death pathway (6 -14). Other galectins have also been reported to trigger death of T cell lines and various T cell subsets, including galectin-2, galectin-3, galectin-8, and galectin-9 (15-19). Relatively little is known about the glycoprotein receptors, glycan ligands, and intracellular death pathways used by these galectins. However, our laboratory has found that galectin-1 and galectin-3 kill different subsets of thymocytes, and use distinct sets...

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Section: Galectin-9-induced T Cell Death Requires Different Glycan LIcontrasting

confidence: 50%

Section: Galectin-9-induced T Cell Death Requires Different Glycan LImentioning

confidence: 99%

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

Earl

Jacobs

et al. 2008

Journal of Biological Chemistry

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135

117

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“…We have also recently determined that malignant T cells from some patients with cutaneous T-cell lymphoma have aberrant cell-surface glycosylation and are thus resistant to galectin-1-induced cell death (8). Specifically, we identified malignant T cells from one patient with a single point mutation in core 2 GnT that abrogated enzyme activity and conferred galectin-1 resistance (46). We found that core 2 GnT is highly expressed in parental PSA + LNCaP cells that are susceptible to galectin-1-induced death and markedly reduced in PSA À LNCaP cells that produce abundant galectin-1 and are resistant to galectin-1-induced cell death.…”

Section: Discussionmentioning

confidence: 97%

O-Glycosylation Regulates LNCaP Prostate Cancer Cell Susceptibility to Apoptosis Induced by Galectin-1

Valenzuela¹,

Pace²,

Cabrera³

et al. 2007

Cancer Research

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Resistance to apoptosis is a critical feature of neoplastic cells. Galectin-1 is an endogenous carbohydrate-binding protein that induces death of leukemia and lymphoma cells, breast cancer cells, and the LNCaP prostate cancer cell line, but not other prostate cancer cell lines. To understand the mechanism of galectin-1 sensitivity of LNCaP cells compared with other prostate cancer cells, we characterized glycan ligands that are important for conferring galectin-1 sensitivity in these cells, and analyzed expression of glycosyltransferase genes in galectin-1-sensitive, prostate-specific antigen-positive (PSA + ) LNCaP cells compared with a galectin-1-resistant PSA À LNCaP subclone. We identified one glycosyltransferase, core 2 N-acetylglucosaminyltransferase, which is downregulated in galectin-1-resistant PSA À LNCaP cells compared with galectin-1-sensitive PSA + LNCaP cells. Intriguingly, this is the same glycosyltransferase required for galectin-1 susceptibility of T lymphoma cells, indicating that similar O-glycan ligands on different polypeptide backbones may be common death trigger receptors recognized by galectin-1 on different types of cancer cells. Blocking O-glycan elongation by expressing A2,3-sialyltransferase 1 rendered LNCaP cells resistant to galectin-1, showing that specific O-glycans are critical for galectin-1 susceptibility. Loss of galectin-1 susceptibility and synthesis of endogenous galectin-1 has been proposed to promote tumor evasion of immune attack; we found that galectin-1-expressing prostate cancer cells killed bound T cells, whereas LNCaP cells that do not express galectin-1 did not kill T cells. Resistance to galectin-1-induced apoptosis may directly contribute to the survival of prostate cancer cells as well as promote immune evasion by the tumor. [Cancer Res 2007;67(13):6155-62]

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“…Gal1 induces apoptosis of activated CD8 T cells (18) and induces Th2 cytokine shifts. Expression of C2GnT (core 2 ␤-1,6-N-acetylglucosaminyltransferase) by T cells, which initiates a second branch on O-glycans, later elongated with poly-N-acetyllactosamine moieties, renders activated T cells susceptible to gal1-induced apoptosis (19,20). Differential glycosylation of Th1, Th2, and Th17 CD4 T cells results in differential sensitivity to gal1-induced apoptosis.…”

mentioning

confidence: 99%

“…On O-glycans, the lectin peanut agglutinin (PNA) recognizes asialo core 1 O-glycans, the substrate on which the enzyme C2GnT adds the second branch of core 2 O-glycans (19,20), later elongated with poly-N-acetyllactosamine moieties, to which gal1 binds. The dTs bound significantly more PNA than the pTs ( Fig.…”

mentioning

confidence: 99%

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

Kopcow

Rosetti²,

Leung³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

102

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The human fetus is not rejected by the maternal immune system despite expressing paternal antigens. Natural killer cells, the major lymphocyte population of the human decidua (dNKs), express genes with immunomodulatory potential. These include galectin-1 (gal1), a lectin with apoptotic activity on activated CD8 ؉ T cells, Th1 and Th17 CD4 ؉ cells. Although many cell types at the maternalfetal interface also produce gal1, its production by dNKs has been used here to study its function in pregnancy. Media conditioned by dNKs containing gal1 induced apoptosis of activated T cells. This effect was blocked by anti-gal1 antibodies. Decidual T (dT) cells but not peripheral T (pT) cells bound gal1 and presented a distinct glycophenotype compatible with sensitivity to gal1. Annexin V staining, TUNEL, and hypodiploidy showed a substantial proportion of apoptotic dT cells. Immunohistochemistry revealed widespread expression of gal1 as well as periglandular apoptotic dT foci that colocalized with dNKs. Thus, secretion of gal1 by dNKs and other decidual cells contributes to the generation of an immuneprivileged environment at the maternal-fetal interface.maternal-fetal tolerance ͉ NK cells ͉ lectin ͉ decidua

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Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death

Cited by 45 publications

References 57 publications

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways

O-Glycosylation Regulates LNCaP Prostate Cancer Cell Susceptibility to Apoptosis Induced by Galectin-1

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

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