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

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).

Human and Murine CD4 T Cell Reactivity to a Complex Antigen: Recognition of the Synthetic Random Polypeptide Glatiramer Acetate

“…A significant secondary in vitro proliferative response was observed in healthy human subjects, confirming an earlier report (21). Surprisingly, this response was strong enough to be detectable in vitro in primary T cells, which usually occurs only with recall Ags such as tetanus toxoid in immunized individuals.…”

“…Many of these sequences will be closely related due to the fact that only one of four amino acids can occupy each position. In accordance with the notion emerging over the past few years that Ag recognition by CD4 T cells is more degenerate than originally thought (20,21,33), individual GA-reactive CD4 T cells are likely to respond to many different possible epitopes. These cross-reactive epitopes may be considered altered peptide ligands for any given T cell with the potential of being superagonists, agonists, partial agonists, antagonists, or null ligands (19).…”

“…This degeneracy has been observed in humans with the use of T cell clones recognizing the 84 -102 immunodominant epitope of MBP using peptides with multiple substitutions of TCR contact residues (20,21). These findings suggest that a random polymer of amino acids with common MHC and TCR contact residues containing frequent spacer, nonbulky amino acids might act as a universal peptide Ag, engaging the TCR in such a manner that the proliferation of many T cells are induced.…”

Identification of Epstein-Barr virus proteins as putative targets of the immune response in multiple sclerosis

“…Indeed, CD8 + T cells dominate MS lesions and are more often clonotypic than CD4 + T cells in MS tissue and CSF (4,5). T cell cross-recognition between virus (e.g., EBV peptides) and myelin antigens was demonstrated on the cellular (46,47) and structural levels (48). Cross-reactivity with viral antigens can trigger autoimmunity in animal models of MS (49).…”

Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

“…Many peptides derived from common viruses share linear sequence homologies with myelin proteins, and in animal models these can induce cross-reactive and potentially pathogenic T cell responses (5)(6)(7)(8)(9)(10). This cross-reactive response reflects the degeneracy of peptide-MHC complex recognition by the TCR, which allows a single receptor to bind a hierarchy of peptide ligands (6,11). However, while commonly discussed as a trigger for autoimmune disease, the pathophysiological significance of molecular mimicry during the natural course of an acute infection remains uncertain (12).…”