Siglec-E is a Critical Inhibitory Receptor Controlling APC Activation and T Cell-Mediated Transplant Rejection
Early after transplantation, inflammation and tissue injury release danger signals that activate myeloid innate immune cells like DCs, driving adaptive immune responses and acute rejection. Current immunosuppressive drugs primarily target T cells, leaving innate immunity inadequately controlled. Siglec-E (SigE), an innate inhibitory receptor, binds sialic acid-carrying ligands to suppress inflammatory responses. In mouse heart transplants, SigE is upregulated in graft-infiltrating myeloid cells, including DCs. Human homologs Sig-7 and Sig-9 are also upregulated in rejecting heart and kidney transplant biopsies. Genetic ablation of SigE in recipients accelerates acute rejection of heart, kidney, and skin allografts. SigE-deficient DCs are more susceptible to activation by danger signals and show enhanced NF-kB activation and TNF-a production, increasing alloreactive T-cell responses. Overexpressing SigE on DCs reduces their activation by DAMPs and their T-cell allostimulatory capacity. Thus, SigE is a crucial inhibitory receptor controlling APC activation and T cell-mediated transplant rejection.