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Updated: Mar 9, 2026
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis
Sabrina Ceeraz1, Petra A Sergent1, Sean F Plummer1
1Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Objective:
The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V-domain Ig-containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1α) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus-prone mouse strain.
Methods:
To evaluate whether genetic deficiency of VISTA affects the development of lupus, we interbred VISTA-deficient mice with Sle1.Sle3 mice, a well-characterized model of systemic lupus erythematosus (SLE).
Results:
We demonstrated that the development of proteinuria and glomerulonephritis in these mice, designated Sle1.Sle3 VISTA-/- mice, was greatly accelerated and more severe compared to that in Sle1.Sle3 and C57BL/6 VISTA-/- mice. Analysis of cells from Sle1.Sle3 VISTA-/- mice showed enhanced activation of splenic CD4+ T cells and myeloid cell populations. No increase in titers of autoantibodies was seen in Sle1.Sle3 VISTA-/- mice. Most striking was a significant increase in proinflammatory cytokines, chemokines, and interferon (IFN)-regulated genes associated with SLE, such as IFNα, IFNγ, tumor necrosis factor, interleukin-10, and CXCL10, in Sle1.Sle3 VISTA-/- mice.
Conclusion:
This study demonstrates for the first time that loss of VISTA in murine SLE exacerbates disease due to enhanced myeloid and T cell activation and cytokine production, including a robust IFNα signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.
Insights
Genetic deficiency of VISTA exacerbates lupus development in mice, leading to accelerated kidney disease and increased inflammation. Enhancing VISTA
Area of Science:
- Immunology
- Autoimmunity
- Molecular Biology
Background:
- VISTA (V-domain Ig-containing suppressor of T cell activation) is a negative checkpoint regulator that suppresses T cell responses and influences myeloid cell activity.
- Targeting negative checkpoint regulators is an established strategy for enhancing anti-tumor immune responses in cancer treatment.
- The role of VISTA in autoimmune diseases, particularly lupus, remains largely unexplored.
Purpose of the Study:
- To investigate the impact of VISTA genetic deficiency on the development and progression of lupus.
- To determine if VISTA plays a role in regulating the immune response in the context of systemic lupus erythematosus (SLE).
Main Methods:
- VISTA-deficient mice were interbred with Sle1.Sle3 mice, a genetic model of lupus.
- The resulting Sle1.Sle3 VISTA-/- mice were monitored for disease development, including proteinuria and glomerulonephritis.
- Immune cell populations (T cells, myeloid cells) and cytokine profiles were analyzed.
Main Results:
- Genetic deficiency of VISTA significantly accelerated and worsened proteinuria and glomerulonephritis in lupus-prone mice.
- Enhanced activation of splenic CD4+ T cells and myeloid cells was observed in Sle1.Sle3 VISTA-/- mice.
- A marked increase in pro-inflammatory cytokines, chemokines, and interferon-regulated genes, including IFNα, was detected.
Conclusions:
- Loss of VISTA exacerbates murine lupus by promoting T cell and myeloid cell activation and increasing pro-inflammatory cytokine production.
- The study highlights a significant IFNα signature associated with VISTA deficiency in lupus.
- These findings support targeting VISTA for therapeutic strategies aimed at enhancing its immunosuppressive activity to treat human lupus.
