Prohibitins function as endogenous ligands for Siglec-9 and negatively regulate TCR signaling upon ligation

Previously we demonstrated that prohibitin-1 and -2 (prohibitins) were expressed on the surface of T cell leukemia cell lines and activated T lymphocytes. In the present study, we found that prohibitins play a role as counter receptors for Siglec-9 expressed on macrophages and dendritic cells. Siglec-9 bound to prohibitins in a sialic acid-independent manner. Mutated Siglec-9 with Arg120 changed to Ala lost the binding activity, suggesting a specific ionic peptide-peptide interaction. Phosphorylation of ERK1/2 in Jurkat cells on treatment with anti-CD3 antibody immobilized beads was markedly diminished on treatment with anti-CD3 antibody and Siglec-9 co-immobilized beads, indicating that engagement of prohibitins with Siglec-9 inhibits ERK1/2 phosphorylation. Phosphorylation of c-Raf was also reduced, maybe due to inhibition of the c-Raf-prohibitin interaction by Siglec-9 ligation. In parallel with inhibition of the ERK cascade, IL-2 production was markedly decreased in Jurkat cells. Thus, this interaction may be a useful immunotherapeutic target.