B7h (ICOS-L) maintains tolerance at the fetomaternal interface

Area of Science:

• Immunology
• Reproductive Immunology
• Maternal-Fetal Medicine

Background:

• Successful pregnancy relies on maternal immune tolerance to the semiallogeneic fetus.
• Mechanisms maintaining this tolerance at the fetomaternal interface are not fully understood.

Purpose of the Study:

• To investigate the role of the Inducible T-cell costimulator (ICOS)-B7h costimulatory pathway in maintaining fetomaternal tolerance.
• To elucidate the specific immune cells and molecular pathways involved in ICOS-B7h-mediated immune regulation during pregnancy.

Main Methods:

• Utilized a murine allogeneic pregnancy model (CBA female × B6 male).
• Administered anti-B7h monoclonal antibody to block the ICOS-B7h pathway.
• Analyzed fetal resorption, survival rates, placental cytokine/marker expression (IDO, TGF-β1, IFN-γ), and immune cell populations (CD4+, CD8+ T cells, CD8+CD103+ cells) in spleen and placenta.
• Employed CD4 and CD8 knockout mouse models.
• Performed adoptive transfer of regulatory CD8+ T cells.

Main Results:

• Blockade of the ICOS-B7h pathway significantly increased fetal resorption and decreased fetal survival.
• Anti-B7h treatment led to reduced placental regulatory markers (IDO, TGF-β1) and increased effector cytokines (IFN-γ).
• Enhanced IFN-γ and granzyme B production by CD8+ T cells was observed in lymphoid organs.
• The detrimental effects of B7h blockade were dependent on CD4+ T cells but not CD8+ T cells, indicating a role for CD8+ T cells in ICOS-B7h pathway regulation.
• A decrease in regulatory CD8+ T cells (CD8+CD103+) was noted post-anti-B7h treatment, and their transfer protected against pregnancy complications.

Conclusions:

• The ICOS-B7h costimulatory pathway is essential for maintaining fetomaternal tolerance.
• B7h blockade abrogates tolerance by promoting CD8+ effector responses and diminishing CD8+ regulatory T cell function at the fetomaternal interface.