Galectin-3 negatively regulates TCR-mediated CD4<sup>+</sup>T-cell activation at the immunological synapse

Chen, Huan‐Yuan; Fermin, Agnes; Vardhana, Santosha A.; Weng, I-Chun; Lo, Kin Fong Robin; Chang, En-Yuh; Maverakis, Emanual; Yang, Ri Yao; Hsu, Daniel K.; Dustin, Michael L.; Liu, Fu‐Tong

doi:10.1073/pnas.0903497106

Cited by 161 publications

(136 citation statements)

References 48 publications

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“…5A). It was reported that the lattice formed by Gal-3 negatively regulates the TCR response by restricting receptor lateral motility (23)(24)(25). These reports support the lack of costimulation in the presence of Gal-3, as well as its inhibitory effect on the Ag-specific T cell response.…”

Section: Gal-3 Antagonizes Ag-specific T Cell Responsesupporting

confidence: 69%

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Tribulatti

Figini

Carabelli

et al. 2012

The Journal of Immunology

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Galectins, a family of mammalian lectins, have emerged as key regulators of the immune response. We previously demonstrated that galectin (Gal)-8, from the tandem-repeat subgroup, exerts two well-defined effects on mouse naive peripheral CD4 T cells: Ag-specific costimulation and Ag-independent proliferation. These stimulatory signals on naive T cells have not been described for any other Gal. Therefore, we investigated whether Gal-1 and Gal-3, two prominent members of the Gal family, share the stimulatory effects exerted by Gal-8 on naive T cells. We found that Gal-1 costimulated Ag-specific T cell responses similarly to Gal-8, as evaluated in the DO11.10 TCROVA-transgenic mouse model, by acting simultaneously on APCs and target CD4 T cells. In contrast, Gal-3 failed to costimulate Ag-specific T cell responses; moreover, it antagonized both Gal-1 and Gal-8 signals. We observed that both Gal-1 and Gal-3 were unable to induce Ag-independent proliferation; however, when two Gal-1 molecules were covalently fused, the resulting chimeric protein efficiently promoted proliferation. This finding indicates that Gal-1 might eventually induce proliferation and, moreover, stresses the requirement of a tandem-repeat structure. Remarkably, a single dose of recombinant Gal-1 or Gal-8 administered together with a suboptimal Ag dose to DO11.10 mice strengthened weak responses in vivo. Taken together, these findings argue for the participation of Gals in the initiation of the immune response and allow the postulation of these lectins as enhancers of borderline Ag responses, thus representing potential adjuvants for vaccine formulations.

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Section: Gal-3 Antagonizes Ag-specific T Cell Responsesupporting

confidence: 69%

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Tribulatti

Figini

Carabelli

et al. 2012

The Journal of Immunology

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“…DEC-205 has been used to identify a population of tolerogenic DC specialized for the induction of Foxp3 1 Treg [27], and for the first time, we showed that a parasite product can increase the surface expression of the CLR DEC-205 directly on T cells. The upregulation of surface expression of galectin-3 is particularly interesting given the recent observation that galectin-3, recruited intracellularly to the immunological synapse, negatively regulates TCR-mediated CD4 1 T-cell activation [28]. Generation of Treg has been associated with suboptimal T-cell activation, resulting from antigen presentation by immature or sub-optimally primed DC [29,30].…”

Section: Discussionmentioning

confidence: 99%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansonisoluble egg antigen (SEA) can induce, together with a Th2 response, TGF-b-dependent Foxp3 expression in naïve CD4 1 T cells from NOD mice. We found that SEA can directly upregulate the expression of surface-bound TGF-b in purified CD4 1 T cells in the absence of accessory cell interactions. In this study, we show that the C-type lectin receptors DEC-205 and galectin-3 were involved in the direct interaction between S. mansoni antigens and CD4 1 T cells. SEA was able to enhance CD4 1 T-cell secretion of bioactive TGF-b in response to TLR2 ligand stimulation, in the absence of APC. We also show that TLR2 expressed on CD4 1 T cells was important for the Foxp3 expression induced by SEA.

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“…However, under chronic conditions, galectin-3 appears to favor the resolution of inflammation, thus limiting tissue injury and promoting repair. In fact, it inhibits lipopolysaccharide-mediated inflammation [64], promotes T-cell apoptosis [65] and negatively regulates TCR-mediated T-cell activation [66,67]. Moreover, MacKinnon et al have shown that up-regulation of galectin-3 expression is a feature of the alternative macrophage (M2) phenotype and that release of galectin-3 by alternatively activated macrophages sustains the M2 phenotype contributing to some of its functions in vivo [68].…”

Section: Galectin-3 As a Disease Mediator: Animal Studiesmentioning

confidence: 99%

Galectin-3 in diabetic patients

Pugliese

Iacobini

Ricci

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Galectin-3 is a versatile molecule which exerts several and sometimes opposite functions in various pathophysiological processes. Recently, galectin-3 has gained attention as a powerful predictor of heart failure and mortality, thus becoming a useful prognostic marker in clinical practice. Moreover, though not specifically investigated in diabetic cohorts, plasma levels of galectin-3 correlated with the prevalence of diabetes and related metabolic conditions, thus suggesting that pharmacological blockade of this lectin might be successful for treating heart failure especially in subjects suffering from these disorders. Indeed, galectin-3 is considered not only as a marker of heart failure, but also as a mediator of the disease, due to its pro-fibrotic action, though evidence comes mainly from studies in galectin-3 deficient mice. However, these studies have provided contrasting results, with either attenuation or acceleration of organ fibrosis and inflammation, depending on the experimental setting and particularly on the levels of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs), of which galectin-3 is a scavenging receptor. In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function of this lectin. Conversely, in experimental models of acute inflammation and fibrosis, galectin-3 deficiency resulted in attenuation of tissue injury. There is a need for prospective studies in diabetic patients specifically investigating the relation of galectin-3 levels with complications and for further animal studies in order to establish the effective role of this lectin in organ damage before considering its pharmacological blockade in the clinical setting.

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Galectin-3 negatively regulates TCR-mediated CD4⁺T-cell activation at the immunological synapse

Cited by 161 publications

References 48 publications

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Galectin-3 in diabetic patients

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Galectin-3 negatively regulates TCR-mediated CD4+T-cell activation at the immunological synapse

Cited by 161 publications

References 48 publications

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Redundant and Antagonistic Functions of Galectin-1, -3, and -8 in the Elicitation of T Cell Responses

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Galectin-3 in diabetic patients

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Galectin-3 negatively regulates TCR-mediated CD4⁺T-cell activation at the immunological synapse