Autoantigen-responsive T cell clones demonstrate unfocused TCR cross-reactivity toward multiple related ligands: Implications for autoimmunity

It has been suggested that the cross-reaction of a single T cell receptor w ith multiple different peptide ligands is a mechanism for maintaining a div erse yet compact immune repertoire. In the context of autoimmune disease it is important to understand how this property is balanced against the maint enance of self-tolerance. Specifically, whether the cross-reactivity inhere nt in the immune system is focused or unfocused will have important consequ ences for the development of autoimmune disease, If cross-reactivity is "fo cused," then in an immune response to a foreign antigen all T cell receptor s that recognize the foreign antigen will cross-react with a specific autoa ntigenic peptide. However, if cross-reactivity is "unfocused," an immune re sponse to a foreign antigen will result in the activation of a small number of self-reactive cells within a larger pool of cells specific for the fore ign antigen. We have tested whether cross-reactivity is focused or unfocuse d by generating a panel of T cell clones that respond to two closely relate d ligands, W144 is an autoantigenic peptide of myelin proteolipid protein, PLP 139-151 (HSLGKWLGHPDKF), and Q144 is an altered peptide of PLP 139-151 bearing a glutamine for tryptophan substitution at position 144, The Q144-r esponsive clones have a broad degree of cross-reactivity with other positio n 144 substituted peptides, We find that despite their characteristic respo nses to Q144 and W144, the patterns of responses of these clones to other s tructurally related ligands are random, demonstrating that cross-reactivity is unfocused in the absence of selection. Maintaining a diverse range of c ross-reactive interactions may limit nonspecific responses to autoantigens. (C) 2000 Academic Press.