Ligand-Receptor Interactions of Galectin-9 and VISTA Suppress Human T Lymphocyte Cytotoxic Activity

Abstract

Acute myeloid leukemia (AML), a blood/bone marrow cancer, is a severe and often fatal malignancy. AML cells are capable of impairing the anti-cancer activities of cytotoxic lymphoid cells. This includes the inactivation of natural killer (NK) cells and killing of T lymphocytes. Here we report for the first time that V-domain Ig-containing suppressor of T cell activation (VISTA), a protein expressed by T cells, recognizes galectin-9 secreted by AML cells as a ligand. Importantly, we found that soluble VISTA released by AML cells enhances the effect of galectin-9, most likely by forming multiprotein complexes on the surface of T cells and possibly creating a molecular barrier. These events cause changes in the plasma membrane potential of T cells leading to activation of granzyme B inside cytotoxic T cells, resulting in apoptosis.

High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells

“…As a result, TGF-β induces galectin-9 production by these cells in a Smad3-dependent manner, the effect which has recently been reported ( 9 ) and confirmed in the present study. Galectin-9 subsequently displays immunosuppressive activities on cytotoxic and helper T cells in the tumour microenvironment as well as on NK cells ( 10 , 17 ). The effects of HMGB1-induced galectin-9 expression were observed in the TLR4-expressing THP-1 human AML cell line ( Figure 1 ) as well as in primary human AML cells expressing this receptor ( Supplementary Figure 6 ).…”

“…Our recent work also suggested that, in Toll-like receptor 4 (TLR4)-expressing cells, HMGB1 induces the production and secretion of transforming growth factor beta type 1 (TGF-b) (9). TGF-b displays both autocrine and paracrine activities and, through the transcription factor Smad3, induces expression of galectin-9, an immunosuppressive protein which impairs the anti-cancer activities of natural killer and cytotoxic T cells (9,10). Galectin-9 is known as a so-called "tandem protein" which contains two ligand/sugar-binding domains fused together by a linker peptide.…”

Ceratothoa oestroides Infection in European Sea Bass: Revealing a Long Misunderstood Relationship

“…Perturbation of the spleen pathways due to infection with C. oestroides shows that the primary local effect is disseminated systemically in the host. Interestingly, among the most upregulated immunity-related genes are the negative elongation factor E , known for its role in inducing the expression of anti-inflammatory genes ( 43 ), and V-type Ig domain-containing suppressor of T cell activation (vista) , which has been recently described to interact with galectin-9, consequently inducing apoptosis in cytotoxic T cells in humans ( 44 ). Although galectin-9 was not upregulated in the spleen, it was found significantly expressed in our samples (mean expression: 1123.9 normalized counts).…”

Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby

“…Recently, galectin-9 has also been reported to be a ligand for VISTA. VISTA mediates galectin-9-induced downregulation of granzyme B release from T cells, trapping granzyme B inside the T cells and leading to apoptosis (16). There is a high likelihood for galectin-9 and soluble VISTA to form multi-protein agglomerates that engage with VISTA on the surface of T cells, which changes the plasma membrane potential and leads to granzyme B mediated self-killing of T cells (16).…”

“…VISTA mediates galectin-9-induced downregulation of granzyme B release from T cells, trapping granzyme B inside the T cells and leading to apoptosis (16). There is a high likelihood for galectin-9 and soluble VISTA to form multi-protein agglomerates that engage with VISTA on the surface of T cells, which changes the plasma membrane potential and leads to granzyme B mediated self-killing of T cells (16). These findings come from studies of the interaction between THP-1 acute myeloid leukemia cells that heavily secrete galectin-9 and soluble VISTA, and Jurkat T cells, which highly express VISTA, so further research is needed to determine if the reported ligand-receptor interaction applies in a broader context.…”