In summary, our results suggest first a direct involvement of CD6–CD166/ALCAM interaction in peripheral T-cell responses induced by cell contact-dependent antigen presentation; second, a role for CD6 in the maintenance of tolerance; and third, an incipient model for the molecular basis underlying CD6 targeting therapies, the latter in line with CD6 susceptibility gene variants for multiple sclerosis (5, 6), Behçet’s disease (46), and CD6 deranged expression in Sjögren’s syndrome patients (47). Here, CD6 is linked to multiple sclerosis.