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

Inna M Yasinska,Giuliano Siligardi,Walter Fiedler,Maxwell Casely-Hayford,Steffen M Berger,Ulrike Raap,Stephanie Schlichtner,Bernhard F Gibbs,Rohanah Hussain,N Helge Meyer,Vadim V Sumbayev,Elizaveta Fasler-Kan,Luigi Calzolai,Jasmin Wellbrock,Luca Varani,Cloe Desmet

doi:10.3389/fimmu.2020.580557

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.

Highlights

Acute myeloid leukemia (AML) is a blood/bone marrow cancer originating from myeloid precursors, which rapidly progresses into a systemic and often a fatal malignancy
In order to assess the possible interactions of V-domain Ig-containing suppressor of T cell activation (VISTA) with galectin-9 we used 96 well Enzyme-Linked Immunosorbent Assay (ELISA) plates coated with goat antiVISTA antibody
We immunoprecipitated VISTA from Jurkat T cells by exposing the plate to Jurkat T cell lysates (Figures 1A, B) as previously described [4]. We found that these cells express VISTA protein, while we could not detect any VISTA in primary natural killer (NK) cell lysates (Figure 1C; a full comparison of fluorescence observed for VISTA in Western blot analysis conducted in Jurkat T, primary human NK, THP1, primary human AML and primary human T cells is presented in Supplementary Figure 1)

Summary

Introduction

Acute myeloid leukemia (AML) is a blood/bone marrow cancer originating from myeloid precursors, which rapidly progresses into a systemic and often a fatal malignancy. Human AML cells operate a variety of biochemical mechanisms which allow them to escape host immune surveillance [1]. These molecular pathways cause impairment of the anti-cancer activities of natural killer (NK) cells and cytotoxic T cells which could otherwise attack and kill AML cells [1, 2]. Galectin-9 has two similar ligand/sugar-binding domains [7, 8]. These domains are fused together by a peptide linker, which could be of three different sizes (due to alternative splicing), that determines the presence of three isoforms of galectin-9 in human cells [7, 8]

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