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A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1[sup.-/-]) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies., Author(s): Sandra M Blois (corresponding author) [1]; Juan M Ilarregui [2, 9]; Mareike Tometten [1, 9]; Mariana Garcia [1]; Arif S Orsal [1]; Rosalia Cordo-Russo [1]; Marta A Toscano [2]; [...]

Interleukin (IL)‐1β has proven to be crucial in the differentiation of human and mouse Th17 cells. Although it has become evident that IL‐1β has potent IL‐17‐inducing effects on CD4+ T cells directly, it has not yet been explored whether IL‐1β can also prime dendritic cells (DCs) for a Th17 instruction program. Here, we show that human immature DCs exposed to IL‐1β promote IL‐17 production in human memory CD4+ T cells. IL‐1β‐primed DCs express high levels of CD14 that mediate IL‐17 production through direct interaction with T cells. Moreover, culturing human CD4+CD45RO+ memory T cells with soluble CD14 is sufficient for the upregulation of retinoic acid‐related orphan receptor‐γ thymus and IL‐17 production. In addition, in a human in situ model using tissue‐resident skin DCs, upregulation of CD14 expression induced by IL‐1β on skin residents DCs promotes IL‐17 production in memory T cells; strongly suggesting the in vivo relevance of this mechanism. Our findings uncover new roles for IL‐1β and CD14, and may therefore have important consequences for the development of new therapies for Th17‐mediated autoimmune diseases and bacterial and fungal pathogenic infections. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates a functional crosstalk between immune and endocrine mechanisms in the modulation of innate and adaptive immunity. However, the impact of thyroid hormones (THs) in the initiation of adaptive immune responses has not yet been examined. Here we investigated the presence of thyroid hormone receptors (TRs) and the impact of THs in the physiology of mouse dendritic cells (DCs), specialized antigen-presenting cells with the unique capacity to fully activate naive T cells and orchestrate adaptive immunity. Both immature and lipopolysaccharide-matured bone marrow-derived DCs expressed TRs at mRNA and protein levels, showing a preferential cytoplasmic localization. Remarkably, physiological levels of triiodothyronine (T3) stimulated the expression of DC maturation markers (major histocompatability complex II, CD80, CD86, and CD40), markedly increased the secretion of interleukin-12, and stimulated the ability of DCs to induce naive T cell proliferation and IFN-γ production in allogeneic T cell cultures. Analysis of the mechanisms involved in these effects revealed the ability of T3 to influence the cytoplasmic-nuclear shuttling of nuclear factor-κB on primed DCs. Our study provides the first evidence for the presence of TRs on bone marrow-derived DCs and the ability of THs to regulate DC maturation and function. These results have profound implications in immunopathology, including cancer and autoimmune manifestations of the thyroid gland at the crossroads of the immune and endocrine systems. [ABSTRACT FROM AUTHOR]

Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17–producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17–differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1–induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1–deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response. [ABSTRACT FROM AUTHOR]

A correction to the article "A pivotal role for galectin-1 in fetomaternal tolerance" that was published in November 18, 2007 issue is presented.

Despite considerable progress in our understanding of the interplay between immune and endocrine systems, the role of thyroid hormones and their receptors in the control of adaptive immunity is still uncertain. Here, we investigated the role of thyroid hormone receptor (TR) beta(1) signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T(3)) resulted in a rapid and sustained increase in Akt phosphorylation independently of phosphatidylinositol 3-kinase activation, which was essential for supporting T(3)-induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TR beta(1) signaling as small interfering RNA-mediated silencing of TR beta(1) expression prevented T(3)-induced DC maturation and IL-12 secretion as well as Akt activation and I kappaB-epsilon degradation. In turn, T(3) up-regulated TR beta(1) expression through mechanisms involving NF-kappaB, suggesting an autocrine regulatory loop to control hormone-dependent TR beta(1) signaling. These findings were confirmed by chromatin immunoprecipitation analysis, which disclosed a new functional NF-kappaB consensus site in the promoter region of the TRB1 gene. Thus, a T(3)-induced NF-kappaB-dependent mechanism controls TR beta(1) expression, which in turn signals DCs to promote maturation and function via an Akt-dependent but PI3K-independent pathway. These results underscore a novel unrecognized target that regulates DC maturation and function with critical implications in immunopathology at the cross-roads of the immune-endocrine circuits.

In the postgenomic era, the study of the glycome-the whole repertoire of saccharides in cells and tissues-has enabled the association of unique glycan structures with specific physiological and pathological processes. The responsibility for deciphering this biological information belongs to endogenous glycan-binding proteins or lectins. Galectin-1, a prototypic member of a family of structurally related proteins, has demonstrated selective antiinflammatory and immunoregulatory effects either by controlling immune cell trafficking, "fine-tuning" dendritic cell physiology and regulating T-cell fate. These regulatory functions mediated by an endogenous glycan-binding protein may contribute to fulfill the needs for immune cell homeostasis, including preservation of fetomaternal tolerance and prevention of collateral damage as a result of microbial invasion or autoimmune pathology. We will discuss here the conceptual framework which led to the study of galectin-glycan lattices as a novel paradigm of immune cell communication in physiological and pathological processes and will highlight selected methods and experimental strategies which have contributed to the study of the immunoregulatory activities of this multifaceted glycan-binding protein both in in vitro and in vivo biological settings., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

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.