Identification of High Potency Microbial and Self Ligands for a Human Autoreactive Class II–restricted T Cell Clone

TLDR

CD4+ class II–restricted T cells specific for self antigens are implicated in most human autoimmune diseases, with molecular mimicry between foreign and self ligands proposed as a mechanism for their activation. This study introduces combinatorial peptide libraries as a tool to identify cross‑reactive ligands for such autoreactive T cells. The authors dissected antigen recognition of a myelin basic protein–specific CD4+ T cell clone by testing its response to 220 11‑mer peptide sublibraries. Artificial peptides discovered through the libraries triggered proliferative responses at lower concentrations than the native MBP(86‑96) peptide, and both self‑ and microbial‑derived ligands, some even more potent, demonstrated that autoreactive CD4+ T cells recognize antigens with high degeneracy, that the original autoantigen is suboptimal, and that unbiased combinatorial libraries can map the full spectrum of stimulatory ligands.

Abstract

CD4+ class II–restricted T cells specific for self antigens are thought to be involved in the pathogenesis of most human autoimmune diseases and molecular mimicry between foreign and self ligands has been implicated as a possible mechanism for their activation. In this report we introduce combinatorial peptide libraries as a powerful tool to identify cross-reactive ligands for these T cells. The antigen recognition of a CD4+ T cell clone (TCC) specific for myelin basic protein peptide (MBP) (86-96) was dissected by the response to a set of 220 11-mer peptide sublibraries. Based on the results obtained with the libraries for each position of the antigen, artificial peptides were found that induced proliferative responses at much lower concentrations than MBP(86-96). In addition stimulatory ligands derived from protein sequences of self and microbial proteins were identified, some of them even more potent agonists than MBP(86-96). These results indicate that: (a) for at least some autoreactive CD4+ T cells antigen recognition is highly degenerate; (b) the autoantigen used to establish the TCC represents only a suboptimal ligand for the TCC; (c) a completely random and unbiased approach such as combinatorial peptide libraries can decrypt the spectrum of stimulatory ligands for a T cell receptor (TCR).