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VISTA Stimulation of VSIG4-Positive Macrophages Strongly Suppresses T Cell Proliferation via Excessive Nitric Oxide
1Innovative Therapeutics Research Institute, College of Medicine, Inje University.
Abstract:
Organ damage and immune deficiency are important problems in sepsis caused by an excessive immune response. There is controversy about the cause of immune suppression. In this study, we investigated the roles of macrophages that exhibit excessive activity on T cell immunity. Peritoneal macrophages from mice with cecal ligation and puncture (CLP)-induced sepsis migrated to different organs. In particular, V-set immunoglobulin (Ig)-domain-containing 4 (VSIG4) positive macrophages appeared in the spleen 48 h after CLP induction. When cocultured with splenic T cells, VSIG4(+) cells inhibited the proliferation of activated T cells through the release of nitric oxide (NO) compared to VSIG4(-) cells. Stimulation of VSIG4(+) cells with V-domain Ig suppressor of T cell activation (VISTA) antibody increased the expression of several cytokine genes and the release of NO, but not phagocytosis, compared to those of hamster IgG-stimulated VSIG4(+) cells. When cocultured with splenic T cells, VISTA-stimulated VSIG4(+) cells induced excessive T cell suppression via more NO secretion compared to hamster IgG-stimulated VSIG4(+) cells. Taken together, the current study demonstrates that VSIG4(+) peritoneal macrophages play important roles in inducing immunosuppression and that VISTA acts as a costimulatory receptor in these cells. These data suggest that blocking the migration of VSIG4(+) cells might alleviate excessive immune activity and that blocking VISTA on VSIG4(+) macrophages might play a crucial role in the development of new therapies to prevent T cell suppression in sepsis.
Insights
Sepsis-induced immune suppression involves V-set immunoglobulin domain-containing 4 (VSIG4) positive macrophages that inhibit T cell proliferation. Blocking VSIG4 migration or V-domain Ig suppressor of T cell activation (VISTA) on these cells may offer new sepsis therapies.
Area of Science:
- Immunology
- Sepsis Pathophysiology
- Macrophage Biology
Background:
- Sepsis causes organ damage and immune deficiency due to an overactive immune response.
- The precise mechanisms driving sepsis-induced immune suppression remain debated.
- Macrophages play a critical role in regulating immune responses during sepsis.
Purpose of the Study:
- To investigate the role of macrophages in T cell immunity during sepsis.
- To identify specific macrophage populations involved in immune suppression.
- To explore the function of V-set immunoglobulin (Ig)-domain-containing 4 (VSIG4) positive macrophages in sepsis.
Main Methods:
- Cecal ligation and puncture (CLP) model in mice to induce sepsis.
- Isolation and characterization of peritoneal macrophages.
- Co-culture experiments with splenic T cells.
- Analysis of T cell proliferation, cytokine gene expression, nitric oxide (NO) release, and phagocytosis.
Main Results:
- VSIG4 positive macrophages migrated to organs, notably the spleen, post-CLP induction.
- VSIG4 positive macrophages inhibited T cell proliferation via nitric oxide (NO) release.
- Stimulation with V-domain Ig suppressor of T cell activation (VISTA) antibody enhanced NO secretion and T cell suppression by VSIG4 positive macrophages.
- VISTA acts as a costimulatory receptor on VSIG4 positive macrophages.
Conclusions:
- VSIG4 positive peritoneal macrophages contribute significantly to sepsis-induced immunosuppression.
- VISTA signaling on VSIG4 positive macrophages exacerbates T cell suppression.
- Targeting VSIG4 positive macrophage migration or VISTA signaling presents potential therapeutic strategies for sepsis.
