Therapeutic potential of TCR antagonists is determined by their ability tomodulate a diverse repertoire of autoreactive T cells

The use of altered peptide ligands (APL) with TCR antagonist properties hol ds promise as an antigen-specific therapy for autoimmune disorders. We are investigating the therapeutic potential of APL in experimental autoimmune e ncephalomyelitis (EAE) using the Ac1-9 peptide of myelin basic protein in H -2(u) mice. Encephalitogenic T cells recognize Ac1-9 using residues 3Gln an d 6Pro as the major TCR contact sites. Use of position 6 APL is compromised by the heterogeneous nature of the Ac1-9-specific repertoire. Here we iden tify two position 3 APL that act as TCR antagonists on transgenic T cells e xpressing Ac1-9-specific TCR and that inhibit EAE in H-2(u) mice. However, the therapeutic capacity of these two APL correlated directly with the abil ity to maximally inhibit activation of a heterogeneous T cell pool. The imp lications of these findings for the requirements for EAE induction, the rel ative contribution of a given T cell subpopulation to pathology and the mec hanism underlying EAE inhibition in this model are discussed.