Development of a Nascent Galectin-1 Chimeric Molecule for Studying the Role of Leukocyte Galectin-1 Ligands and Immune Disease Modulation

Abstract

Galectin-1 (Gal-1), a β-galactoside–binding lectin, plays a profound role in modulating adaptive immune responses by altering the phenotype and fate of T cells. Experimental data showing recombinant Gal-1 (rGal-1) efficacy on T cell viability and cytokine production, nevertheless, is controversial due to the necessity of using stabilizing chemicals to help retain Gal-1 structure and function. To address this drawback, we developed a mouse Gal-1 human Ig chimera (Gal-1hFc) that did not need chemical stabilization for Gal-1 ligand recognition, apoptosis induction, and cytokine modulation in a variety of leukocyte models. At high concentrations, Gal-1hFc induced apoptosis in Gal-1 ligand+ Th1 and Th17 cells, leukemic cells, and granulocytes from synovial fluids of patients with rheumatoid arthritis. Importantly, at low, more physiologic concentrations, Gal-1hFc retained its homodimeric form without losing functionality. Not only did Gal-1hFc–binding trigger IL-10 and Th2 cytokine expression in activated T cells, but members of the CD28 family and several other immunomodulatory molecules were upregulated. In a mouse model of contact hypersensitivity, we found that a non-Fc receptor-binding isoform of Gal-1hFc, Gal-1hFc2, alleviated T cell-dependent inflammation by increasing IL-4+, IL-10+, TGF-β+, and CD25high/FoxP3+ T cells, and by decreasing IFN-γ+ and IL-17+ T cells. Moreover, in human skin-resident T cell cultures, Gal-1hFc diminished IL-17+ T cells and increased IL-4+ and IL-10+ T cells. Gal-1hFc will not only be a useful new tool for investigating the role of Gal-1 ligands in leukocyte death and cytokine stimulation, but for studying how Gal-1–Gal-1 ligand binding shapes the intensity of immune responses.

The Leukocyte Activation Receptor CD69 Controls T Cell Differentiation through Its Interaction with Galectin-1

“…Thus, besides the induction of apoptosis, nonapoptotic mechanisms might contribute to the immunosuppressive effects of this protein. In accord with this, similar results were observed when low concentrations of Gal-1-human Fc were incubated with human skin-resident memory T cells, which dramatically lowered the numbers of IL-17-producing T cells (25). Depending on the dose of recombinant Gal-1 treatment, the effects could be different (25,37).…”

“…In accord with this, similar results were observed when low concentrations of Gal-1-human Fc were incubated with human skin-resident memory T cells, which dramatically lowered the numbers of IL-17-producing T cells (25). Depending on the dose of recombinant Gal-1 treatment, the effects could be different (25,37). In this regard, an irreversible dimeric form of Gal-1 is a potent inducer of apoptosis in T cells (38).…”

“…Gal-1 ligands are absent from naive mouse T cells but highly expressed on activated CD4 ϩ T cells in lymph nodes (LNs) draining antigen-sensitive skin (25). To assess the possible association of Gal-1 with CD69 in mouse cells, we performed binding assays with naive and PMA-activated CD4 ϩ T cells from WT and CD69-deficient mice.…”

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

“…Here, we demonstrate that psoriasis patients have low expression of gal-1 in peripheral blood myeloid DCs and in LCs of lesional and non-lesional skin that together with previous studies in animal models [34] indicate an important role of gal-1 in the immunopathogenesis of psoriasis. The positive role of gal-1 in IL-10 production has been proposed as one of the mechanisms involved in the inhibition of Th1 and Th17 responses [34][35][36] The co-culture experiments showed that galectin inhibition increases IFN-gamma production by CD4+ T cells in response to antigen presentation by DCs, suggesting that galectins also regulate the production of pro-inflammatory cytokines. Interestingly, IFN-gamma production was decreased by addition of recombinant gal-1 to autologous co-cultures of PBLs with moDCs from psoriasis patients.…”

Galectin-1 inhibits the viability, proliferation, and Th1 cytokine production of nonmalignant T cells in patients with leukemic cutaneous T-cell lymphoma

“…8,9 Gal-1 functions as a homodimer with affinity for N-acetyllactosamine-bearing glycoproteins on effector T cells that, on engagement, induces proapoptotic and/or immunosuppressive activities. 10,11 Gal-1-binding interactions induce deletion of pro-inflammatory T helper (Th)-1 and Th17 cells but spare naive, regulatory, and Th2 cells, leading to a tolerogenic environment that favors tumor immune escape. 12,13 Indeed, in patients with Hodgkin disease, increased Gal-1 expression is correlated with poor prognoses and implicated as a biomarker of disease progression.…”