Competitive binding of CD226/TIGIT with poliovirus receptor regulates macrophage polarization and is involved in vascularized skin graft rejection

End-stage organ failure often requires solid organ transplantation. Nevertheless, transplant rejection remains an unresolved issue. The induction of donor-specific tolerance is the ultimate goal in transplantation research. In this study, an allograft vascularized skin rejection model using BALB/c-C57/BL6 mice was established to evaluate the regulation of the poliovirus receptor signaling pathway using CD226 knockout or T cell immunoglobulin and ITIM domain (TIGIT)-crystallizable fragment (Fc) recombinant protein treatment. In the TIGIT-Fc-treated and CD226 knockout groups, graft survival time prolonged significantly, with a regulatory T cell proportion increase and M2-type macrophage polarization. Donorreactive recipient T cells became hyporesponsive while responding normally after a thirdparty antigen challenge. In both groups, serum interleukin (IL)-1 & beta;, IL-6, IL-12p70, IL-17A, tumor necrosis factor-& alpha;, interferon gamma, and monocyte chemoattractant protein-1 levels decreased, and the IL-10 level increased. In vitro, M2 markers, such as Arg1 and IL-10, were markedly increased by TIGIT-Fc, whereas iNOS, IL-1 & beta;, IL-6, IL-12p70, tumor necrosis factor-& alpha;, and interferon gamma levels decreased. CD226-Fc exerted the opposite effect. TIGIT suppressed TH1 and TH17 differentiation by inhibiting macrophage SHP-1 phosphorylation and enhanced ERK1/2-MSK1 phosphorylation and nuclear translocation

Automated summary

This study established a transplantation rejection model to evaluate the regulation of the poliovirus receptor signaling pathway using CD226 knockout or TIGIT-Fc recombinant protein treatment. The results showed that TIGIT-Fc treatment and CD226 knockout prolonged graft survival time, increased regulatory T cell proportion, and induced M2-type macrophage polarization. Donor-reactive recipient T cells became hyporesponsive but still responded normally to a third-party antigen challenge.