Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.

The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of ß1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.

Suppression of age-related salivary gland autoimmunity by glycosylation-dependent galectin-1-driven immune inhibitory circuits.

Aging elicits quantitative and qualitative changes in different immune components, leading to disruption of tolerogenic circuits and development of autoimmune disorders. Galectin-1 (Gal1), an endogenous glycan-binding protein, has emerged as a regulator of immune cell homeostasis by shaping the fate of myeloid and lymphoid cells. Here, we demonstrate that aged Gal1-null mutant (Lgals1-/- ) mice develop a spontaneous inflammatory process in salivary glands that resembles Sjögren's syndrome. This spontaneous autoimmune phenotype was recapitulated in mice lacking ß1,6N-acetylglucosaminyltransferase V (Mgat5), an enzyme responsible for generating ß1,6-branched complex N-glycans, which serve as a major ligand for this lectin. Lack of Gal1 resulted in CD11c+ dendritic cells (DCs) with higher immunogenic potential, lower frequency of Foxp3+ regulatory T cells (Tregs), and increased number of CD8+ T cells with greater effector capacity. Supporting its tolerogenic activity, Gal1 expression decreased with age in autoimmunity-prone nonobese diabetic (NOD) mice. Treatment with recombinant Gal1 restored tolerogenic mechanisms and reduced salivary gland inflammation. Accordingly, labial biopsies from primary Sjögren's syndrome patients showed reduced Gal1 expression concomitant with higher number of infiltrating CD8+ T cells. Thus, endogenous Gal1 serves as a homeostatic rheostat that safeguards immune tolerance and prevents age-dependent development of spontaneous autoimmunity.

Translating the 'Sugar Code' into Immune and Vascular Signaling Programs.

The vast range and complexity of glycan structures and their dynamic variations in health and disease have presented formidable challenges toward understanding the biological significance of these molecules. Despite these limitations, compelling evidence highlights a major role for galectins, a family of soluble glycan-binding proteins, as endogenous decoders that translate glycan-containing information into a broad spectrum of cellular responses by modulating receptor clustering, reorganization, endocytosis, and signaling. Here, we underscore pioneer findings and recent advances in understanding the biology of galectin-glycan interactions in myeloid, lymphoid, and endothelial compartments, highlighting important pathways by which these multivalent complexes control immune and vascular programs. Implementation of novel glycoanalytical approaches, as well as the use of genetically engineered cell and organism models, have allowed glycans and galectins to be explored across a range of cellular processes.

Spatiotemporal regulation of galectin-1-induced T-cell death in lamina propria from Crohn's disease and ulcerative colitis patients.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic, relapsing intestinal inflammation. Galectin-1 (Gal-1) is an endogenous lectin with key pro-resolving roles, including induction of T-cell apoptosis and secretion of immunosuppressive cytokines. Despite considerable progress, the relevance of Gal-1-induced T-cell death in inflamed tissue from human IBD patients has not been ascertained. Intestinal biopsies and surgical specimens from control patients (n = 52) and patients with active or inactive IBD (n = 97) were studied. Gal-1 expression was studied by RT-qPCR, immunoblotting, ELISA and immunohistochemistry. Gal-1-specific ligands and Gal-1-induced apoptosis of lamina propria (LP) T-cells were determined by TUNEL and flow cytometry. We found a transient expression of asialo core 1-O-glycans in LP T-cells from inflamed areas (p < 0.05) as revealed by flow cytometry using peanut agglutinin (PNA) binding and assessing dysregulation of the core-2 ß 1-6-N-acetylglucosaminyltransferase 1 (C2GNT1), an enzyme responsible for elongation of core 2 O-glycans. Consequently, Gal-1 binding was attenuated in CD3+CD4+ and CD3+CD8+ LP T-cells isolated from inflamed sites (p < 0.05). Incubation with recombinant Gal-1 induced apoptosis of LP CD3+ T-cells isolated from control subjects and non-inflamed areas of IBD patients (p < 0.05), but not from inflamed areas. In conclusion, our findings showed that transient regulation of the O-glycan profile during inflammation modulates Gal-1 binding and LP T-cell survival in IBD patients.

Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10.

Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.

Inflammation Controls Sensitivity of Human and Mouse Intestinal Epithelial Cells to Galectin-1.

Galectins play key roles in the inflammatory cascade. In this study, we aimed to analyze the effect of galectin-1 (Gal-1) in the function of intestinal epithelial cells (IECs) isolated from healthy and inflamed mucosa. IECs isolated from mice or patients with inflammatory bowel diseases (IBD) were incubated with different pro-inflammatory cytokines, and Gal-1 binding, secretion of homeostatic factors and viability were assessed. Experimental models of food allergy and colitis were used to evaluate the in vivo influence of inflammation on Gal-1 binding and modulation of IECs. We found an enhanced binding of Gal-1 to: (a) murine IECs exposed to IL-1ß, TNF, and IL-13; (b) IECs from inflamed areas in intestinal tissue from IBD patients; (c) small bowel of allergic mice; and (d) colon from mice with experimental colitis. Our results showed that low concentrations of Gal-1 favored a tolerogenic micro-environment, whereas high concentrations of this lectin modulated viability of IECs through mechanisms involving activation of caspase-9 and modulation of Bcl-2 protein family members. Our results showed that, when added in the presence of diverse pro-inflammatory cytokines such as tumor necrosis factor (TNF), IL-13 and IL-5, Gal-1 differentially promoted the secretion of growth factors including thymic stromal lymphopoietin (TSLP), epidermal growth factor (EGF), IL-10, IL-25, and transforming growth factor (TGF-ß1 ). In conclusion, we found an augmented binding of Gal-1 to IECs when exposed in vitro or in vivo to inflammatory stimuli, showing different effects depending on Gal-1 concentration. These findings highlight the importance of the inflammatory micro-environment of mucosal tissues in modulating IECs susceptibility to the immunoregulatory lectin Gal-1 and its role in epithelial cell homeostasis.

Protective Efficacy of the Epitope-Conjugated Antigen N-Tc52/TSkb20 in Mitigating Trypanosoma cruzi Infection through CD8+ T-Cells and IFNγ Responses.

Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health challenge affecting millions in Latin America and worldwide. Although significant progress has been made in vector control, no vaccine exists to prevent infection or mitigate disease pathogenesis. We developed a rationally designed chimeric protein vaccine, N-Tc52/TSkb20, incorporating immunodominant epitopes from two T. cruzi antigens, the amino-terminal portion of Tc52 and the TSkb20 epitope derived from trans-sialidase. The objectives of this study were to construct and characterize the antigen and evaluate its protective potential in an immunoprophylactic murine model of T. cruzi infection. The N-Tc52/TSkb20 protein was recombinantly expressed in E. coli and its identity was confirmed using mass spectrometry and Western blotting. Immunization with the chimeric protein significantly controlled parasitemia and reduced the heart, colon, and skeletal muscle parasite burdens compared to non-vaccinated mice. Protection was superior to vaccination with the individual parental antigen components. Mechanistically, the vaccine induced potent CD8+ T-cell and IFNγ responses against the incorporated epitopes and a protective IgG antibody profile. A relatively low IL-10 response favored early parasite control. These results validate the promising multi-epitope approach and support the continued development of this type of rational vaccine design strategy against Chagas disease.

Galectin-1 confers immune privilege to human trophoblast: implications in recurrent fetal loss.

Mechanisms accounting for the protection of the fetal semi-allograft from maternal immune cells remain incompletely understood. In previous studies, we showed that galectin-1 (Gal1), an immunoregulatory glycan-binding protein, hierarchically triggers a cascade of tolerogenic events at the mouse fetomaternal interface. Here, we show that Gal1 confers immune privilege to human trophoblast cells through the modulation of a number of regulatory mechanisms. Gal1 was mainly expressed in invasive extravillous trophoblast cells of human first trimester and term placenta in direct contact with maternal tissue. Expression of Gal1 by the human trophoblast cell line JEG-3 was primarily controlled by progesterone and pro-inflammatory cytokines and impaired T-cell responses by limiting T cell viability, suppressing the secretion of Th1-type cytokines and favoring the expansion of CD4(+)CD25(+)FoxP3(+) regulatory T (T(reg)) cells. Targeted inhibition of Gal1 expression through antibody (Ab)-mediated blockade, addition of the specific disaccharide lactose or retroviral-mediated siRNA strategies prevented these immunoregulatory effects. Consistent with a homeostatic role of endogenous Gal1, patients with recurrent pregnancy loss showed considerably lower levels of circulating Gal1 and had higher frequency of anti-Gal1 auto-Abs in their sera compared with fertile women. Thus, endogenous Gal1 confers immune privilege to human trophoblast cells by triggering a broad tolerogenic program with potential implications in threatened pregnancies.

Lack of TNFR p55 results in heightened expression of IFN-γ and IL-17 during the development of reactive arthritis.

Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55(-/-) mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-γ and IL-17 in arthritic joints of TNFRp55(-/-) mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-γ production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55(-/-) mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4(+)IL-17(+), CD4(+)IFN-γ(+), and IL-17(+)IFN-γ(+) cells in TNFRp55(-/-) mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-γ resulted in reduced joint histological scores in TNFRp55(-/-) mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-γ and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege.

Despite the existence of tumor-specific immune cells, most tumors have devised strategies to avoid immune attack. We demonstrate here that galectin-1 (Gal-1), a negative regulator of T cell activation and survival, plays a pivotal role in promoting escape from T cell-dependent immunity, thus conferring immune privilege to tumor cells. Blockade of immunosuppressive Gal-1 in vivo promotes tumor rejection and stimulates the generation of a tumor-specific T cell-mediated response in syngeneic mice, which are then able to resist subsequent challenge with wild-type Gal-1-sufficient tumors. Our data indicate that Gal-1 signaling in activated T cells constitutes an important mechanism of tumor-immune escape and that blockade of this inhibitory signal can allow for and potentiate effective immune responses against tumor cells, with profound implications for cancer immunotherapy.

Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina.

BACKGROUND: The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHODS: We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS: The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n = 8), whereas only 37.5% (n = 3) of the nodules with RAS and 17% (n = 1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION: The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.

Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina. / Testeo de mutaciones en nódulos tiroideos con citología indeterminada: estudio prospectivo de 112 pacientes en Argentina.

BACKGROUND: The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHOD: We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS: The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n=8), whereas only 37.5% (n=3) of the nodules with RAS and 17% (n=1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION: The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.

Oligonucleotide IMT504 Improves Glucose Metabolism and Controls Immune Cell Mediators in Female Diabetic NOD Mice.

Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta cells. A potential treatment for this disease should address the immune attack on beta cells and their preservation/regeneration. The objective of this study was to elucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able to ameliorate diabetes in NOD mice and to provide further understanding of its mechanism of action. We found that IMT504 restores glucose homeostasis in a diabetes mouse model similar to human type 1 diabetes, by regulating expression of immune modulatory factors and improving beta cell function. IMT504 treatment markedly improved fasting glycemia, insulinemia, and homeostatic model assessment of beta cell function (HOMA-Beta cell) index. Moreover, this treatment increased islet number and decreased apoptosis, insulitis, and CD45+ pancreas-infiltrating leukocytes. In a long-term treatment, we observed improvement of glucose metabolism up to 9 days after IMT504 cessation and increased survival after 15 days of the last IMT504 injection. We postulate that interleukin (IL)-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may function as mediators of this immunomodulatory action. Overall, these results validate the therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible downstream mediators of its immunomodulatory effect.

Control of intestinal inflammation by glycosylation-dependent lectin-driven immunoregulatory circuits.

Diverse immunoregulatory circuits operate to preserve intestinal homeostasis and prevent inflammation. Galectin-1 (Gal1), a ß-galactoside-binding protein, promotes homeostasis by reprogramming innate and adaptive immunity. Here, we identify a glycosylation-dependent "on-off" circuit driven by Gal1 and its glycosylated ligands that controls intestinal immunopathology by targeting activated CD8+ T cells and shaping the cytokine profile. In patients with inflammatory bowel disease (IBD), augmented Gal1 was associated with dysregulated expression of core 2 ß6-N-acetylglucosaminyltransferase 1 (C2GNT1) and α(2,6)-sialyltransferase 1 (ST6GAL1), glycosyltransferases responsible for creating or masking Gal1 ligands. Mice lacking Gal1 exhibited exacerbated colitis and augmented mucosal CD8+ T cell activation in response to 2,4,6-trinitrobenzenesulfonic acid; this phenotype was partially ameliorated by treatment with recombinant Gal1. While C2gnt1-/- mice exhibited aggravated colitis, St6gal1-/- mice showed attenuated inflammation. These effects were associated with intrinsic T cell glycosylation. Thus, Gal1 and its glycosylated ligands act to preserve intestinal homeostasis by recalibrating T cell immunity.

Dissecting the signal transduction pathways triggered by galectin-glycan interactions in physiological and pathological settings.

Galectins are a family of evolutionarily conserved animal lectins with pleiotropic functions and widespread distribution. Fifteen members have been identified in a wide variety of cells and tissues. Through recognition of cell surface glycoproteins and glycolipids, these endogenous lectins can trigger a cascade of intracellular signaling pathways capable of modulating cell differentiation, proliferation, survival, and migration. These cellular events are critical in a variety of biological processes including embryogenesis, angiogenesis, neurogenesis, and immunity and are substantially altered during tumorigenesis, neurodegeneration, and inflammation. In addition, galectins can modulate intracellular functions and this effect involves direct interactions with distinct signaling pathways. In this review, we discuss current knowledge on the intracellular signaling pathways triggered by this multifunctional family of beta-galactoside-binding proteins in selected physiological and pathological settings. Understanding the "galectin signalosome" will be essential to delineate rational therapeutic strategies based on the specific control of galectin expression and function.

Functions of cell surface galectin-glycoprotein lattices.

Programmed remodeling of cell surface glycans by the sequential action of specific glycosyltransferases can control biological processes by generating or masking ligands for endogenous lectins. Galectins, a family of animal lectins with affinity for beta-galactosides, can form multivalent complexes with cell surface glycoconjugates and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival. Recent efforts involving genetic or biochemical manipulation of O-glycosylation and N-glycosylation pathways, as well as blockade of the synthesis of endogenous galectins, have illuminated essential roles for galectin-glycoprotein lattices in the control of biological processes including receptor turnover and endocytosis, host-pathogen interactions, and immune cell activation and homeostasis.

Dissecting the pathophysiologic role of endogenous lectins: glycan-binding proteins with cytokine-like activity?

Several families of endogenous glycan-binding proteins have been implicated in a wide variety of immunological functions including first-line defence against pathogens, cell trafficking, and immune regulation. These include, among others, the C-type lectins (collectins, selectins, mannose receptor, and others), S-type lectins (galectins), I-type lectins (siglecs and others), P-type lectins (phosphomannosyl receptors), pentraxins, and tachylectins. This review will concentrate on the immunoregulatory roles of galectins (particularly galectin-1) and collectins (mannose-binding lectins and surfactant proteins) to illustrate the ability of endogenous glycan-binding proteins to act as cytokines, chemokines or growth factors, and thereby modulating innate and adaptive immune responses under physiological or pathological conditions. Understanding the pathophysiologic relevance of endogenous lectins in vivo will reveal novel targets for immunointervention during chronic infection, autoimmunity, transplantation and cancer.

Untangling Galectin-Driven Regulatory Circuits in Autoimmune Inflammation.

Although progress has been made in understanding the mechanisms implicated in the pathogenesis of autoimmune inflammation, studies aimed at identifying the mediators of these pathways will be necessary to develop more selective therapies. Galectins, a family of glycan-binding proteins, play central roles in immune cell homeostasis. Whereas some members of this family trigger regulatory programs that promote resolution of inflammation, others contribute to perpetuate autoimmune processes. We discuss the roles of endogenous galectins and their specific glycosylated ligands in shaping autoimmune responses by fueling, extinguishing, or rewiring immune circuits. Understanding the relevance of galectin-glycan interactions in autoimmune inflammation could help to uncover novel pathways of tolerance breakdown, define molecular signatures for patient stratification and therapy responses, and open new avenues for immune intervention.

Impact of protein-glycan interactions in the regulation of autoimmunity and chronic inflammation.

Protein-glycan interactions control essential immunological processes, including T-cell activation, differentiation and survival. Galectins, carbohydrate-binding proteins, defined by shared consensus amino acid sequences and affinity for beta-galactose-containing oligosaccharides, participate in a wide spectrum of immunological processes. These carbohydrate-binding proteins regulate the development of pathogenic T-cell responses by influencing T-cell survival, activation and cytokine secretion. Administration of recombinant galectins or their genetic delivery modulate the development and severity of chronic inflammatory responses in experimental models of autoimmunity by triggering different and potentially overlapping immunoregulatory mechanisms. Given the potential use of galectins as novel anti-inflammatory agents or targets for immunosuppressive drugs, we will summarize here recent findings on the influence of these carbohydrate-binding proteins in autoimmune and chronic inflammatory disorders.

[How do protein-glycan interactions regulate T-cell physiology?]. / Interacción entre proteínas y glicanos en la regulación fisiológica de las células T.

Recent evidence indicates that protein-glycan interactions play a critical role in different events associated with the physiology of T-cell responses including thymocyte maturation, T-cell activation, lymphocyte migration and T-cell apoptosis. Glycans decorating T-cell surface glycoproteins can modulate T-cell physiology by specifically interacting with endogenous lectins including selectins and galectins. These endogenous lectins are capable of recognizing sugar structures localized on T-cell surface glycoproteins and trigger different signal transduction pathways leading to differentiation, proliferation, cell cycle regulation or apoptosis. Protein-carbohydrate interactions may be controlled at different levels, including regulated expression of lectins during T-cell maturation and differentiation and the spatio-temporal regulation of glycosyltransferases and glycosidases, which create and modify sugar structures present in T-cell surface glycoproteins. This article briefly reviews the mechanisms by which protein-carbohydrate interactions modulate immunological processes such as T-cell activation, migration and apoptosis.