CD6 is a type 1 transmembrane glycoprotein with three extracellular SRCR domains that functions as a co-stimulatory receptor in T cell activation. Its primary ligand is CD166 (ALCAM), an IgSF member expressed on antigen-presenting cells and other tissues. CD6's long cytoplasmic tail contains tyrosine residues that, upon phosphorylation, recruit signaling molecules like SLP76 and SHP1. The CD6-ALCAM interaction promotes T cell activation and downstream MAPK signaling, influencing proliferation, differentiation, and survival. Importantly, CD6 regulates effector T cell (Teff) activity and trafficking, making it a key checkpoint in autoimmunity. Blocking the CD6-ALCAM pathway selectively inhibits pathogenic Teff cells while preserving Treg function, offering a potential therapeutic strategy for autoimmune diseases.