Blocking MHC class II on human endothelium mitigates acute rejection

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Acute allograft rejection is primarily mediated by CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I MHC molecules.
• Human CTL development during rejection can occur within the graft via circulating CD8+ effector memory T cells (TEM) recognizing graft endothelial cell (EC) class I MHC.
• The mechanisms underlying this intra-graft CTL development pathway are not fully understood.

Purpose of the Study:

• To investigate the role of CD4+ TEM cells in supporting CD8+ TEM cell-driven acute allograft rejection targeting graft EC.
• To elucidate the contribution of EC class II MHC molecules in activating CD4+ TEM cells for allograft rejection.

Main Methods:

• Utilized immunodeficient mouse models with human artery grafts to assess the impact of blocking EC HLA-DR (class II MHC).
• Employed siRNA knockdown and CRISPR/Cas9 gene editing to ablate class II MHC molecules on ECs for in vitro and in vivo studies.
• Developed synthetic microvessels from modified ECs lacking class II MHC for evaluating protection against T cell-mediated destruction.

Main Results:

• Blocking EC HLA-DR on human artery grafts reduced CD8+ CTL development and acute rejection in vivo.
• Ablation of EC class II MHC molecules prevented CD4+ TEM cells from helping CD8+ TEM cells differentiate into CTL in vitro.
• Synthetic microvessels lacking EC class II MHC showed significant protection from CD8+ T cell-mediated destruction in vivo.

Conclusions:

• Host CD4+ TEM cells, activated by graft EC class II MHC molecules, provide essential help for CD8+ TEM cell-mediated rejection targeting graft EC class I MHC.
• This CD4+ T cell-dependent pathway is a critical mechanism in acute allograft rejection involving intra-graft CTL development.