VISTA deficiency attenuates antibody-induced arthritis and alters macrophage gene expression in response to simulated immune complexes

Abstract

BackgroundIn addition to activated T cells, the immune checkpoint inhibitor “V domain-containing Ig suppressor of T-cell activation” (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated.MethodsVISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages.ResultsVISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritis patients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn).ConclusionsVISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1474-y) contains supplementary material, which is available to authorized users.

VISTA: Coming of age as a multi-lineage immune checkpoint

“…From the perspective of immune cell function, there are interesting parallels between VISTA and PSGL‐1 on the outcome of immune responses. For example, VISTA deficiency or targeting, and PSGL‐1‐Ig can all ameliorate mouse models of arthritis . VISTA‐ or PSG‐L1‐targeting antibodies can also inhibit GVHD induction by inducing T cell death .…”

VISTA: A novel immunotherapy target for normalizing innate and adaptive immunity

“…?δ T cells. A more recent study revealed the unexpected finding that VISTA-deficiency or anti-VISTA treatment can profoundly ameliorate the induction of collagen-antibody induced arthritis in mice despite enhanced activation of VISTA −/− myeloid cells [19]. The authors attributed this puzzling therapeutic effect to the interference with the C5a signaling pathway, where VISTA −/− macrophages had reduced expression of C5aR1, and therefore signaling and migration.…”

“…Exacerbated GVHD [13] -Prevention of GVHD induction [5] Enhanced experimental asthma [22] -Ameliorates experimental asthma [22] Reduced Collagen-antibody-induced arthritis (CAIA) [19] -Reduced Collagen-antibody-induced arthritis (CAIA) [16] Increased leukocyte infiltration into non-lymphoid tissues [14,33] -Reduction in tumor MDSCs Reduced tumor growth [4,33] -Increased encephalitogenic T cell responses (Th 17 ) in EAE models [14] Reduced EAE induction [Unpublished] Enhanced Lupus nephritis disease [16,17] Ameliorate Lupus nephritis [Unpublished] Enhanced T cell responses [13] Reduced T cell responses [5,13] Reduced iTreg differentiation [24,33] -Semin Immunol. Author manuscript; available in PMC 2020 May 18.…”

The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation

“…One study noted the role of VISTA in regulating the expression of the C5a receptor on neutrophils and bone marrow-derived macrophages and reported that VISTA deficiency or treatment with an immuno-suppressive VISTA mAb (clone 8G8) resulted in attenuated disease in the collagen-II antibody-induced arthritis (CAIA) model. 61 The molecular mechanisms and the relevance of this finding to human arthritis remain to be investigated. Another study by Yoon et al has revealed a role of DD-1α/VISTA in facilitating the clearance of apoptotic cells by phagocytes via homotypic interactions between VISTA expressed on apoptotic cells and phagocytes.…”