Alanine-substituted peptide ligands differ greatly in their ability to activate autoreactive T-cell subsets specific for the wild-type peptide

Alanine-substituted peptide ligands (APLs) have the potential to reduce or block autoreactive T-cell activation. Most previous investigations aimed at either identification of the amino acid residue within a peptide ligand th at is critical for T-cell activation or characterization of inhibitory APLs have analyzed the effects of APLs on one, or a limited number, of T-cell l ines. In this study, we compared the effects of a panel of peptides on the proliferative and activation responses of one T-cell line as well as the ef fects of one peptide on the responses of a panel of T-cell lines. This stud y reveals that the T cells that comprise the T-cell population that respond s to a specific peptide are heterogeneous in that an APL may fail to induce a response in some of these T cells although it is capable of inducing a r esponse in the others. Moreover, APLs can induce T-cell activation, in term s of production of IL-2 and/or TNF-alpha(, in the absence of appreciable ce ll proliferation. Indeed, despite being poor stimulators in proliferation a ssays, most APLs readily induce production of TNF-alpha. Our results demons trate that the net outcome of APL treatment in vivo represents the sum of d iverse effects, which may not be revealed completely by limited and randoml y chosen in vitro assays. (C) 1999 Elsevier Science B.V.. All rights reserv ed.