Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87–99)

Abstract

We have examined the functional consequences induced by interaction of DR2a-restricted myelin basic protein (MBP) (87-99)-specific T cell clones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87-99). The immunodominant MBP peptide (87-99) has been implicated as a candidate antigen in multiple sclerosis (MS) by several lines of evidence. In the present study, we have defined the T cell receptor (TCR) contact residues for DR2a-restricted, (87-99)-specific T helper type 1 T cells to design APL suitable to modify the functions of such T cells potentially relevant for the pathogenesis of MS. We show that neutral (L-alanine substitutions) or conservative exchanges of the primary and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin-2 receptor up-regulation to anergy induction and TCR antagonism. The potential usefulness of APL as an immunomodulating therapy for DR2+ MS patients is discussed.

Combinatorial Peptide Libraries and Biometric Score Matrices Permit the Quantitative Analysis of Specific and Degenerate Interactions Between Clonotypic TCR and MHC Peptide Ligands

“…TCC TL3A6 was established with myelin basic protein (MBP) from PBMC of a patient with MS and recognizes the immunodominant epitope MBP 87-99 (VHFFKNIVTPRTP) in the context of DR2a (DR␣ ϩ DRB5*0101). The TCC has been extensively characterized for recognition of numerous altered peptides derived from MBP 87-99 as well as other molecular mimics (25,31,32,35,36). The TCR usage is TCRAV18 and TCRBV5S1.…”

Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators

“…9 Altered peptide ligands (APL), which are analogues of MBP epitopes (i.e. MBP [1][2][3][4][5][6][7][8][9][10][11] MBP 87-99 , MBP [84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] , MBP [87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106] , and MBP [83][84][85][86][87][88][89][90][91][92]…”

Fine Specificity of T Cells Reactive to Human PDC-E2 163-176 Peptide, the Immunodominant Autoantigen in Primary Biliary Cirrhosis: Implications for Molecular Mimicry and Cross-Recognition Among Mitochondrial Autoantigens

“…Molecular mimicry between foreign and self-antigens have been implicated as a possible mechanism for the activation of these self-reactive T cells. [14][15][16][17][18][19] Previously, we illustrated the evidence of molecular mimicry at the T-cell clonal level in PBC; one molecular mimicry peptide derived from Escherichia coli PDC-E2 activated a human PDC-E2 163-176 -reactive cloned T-cell line generated from a patient with PBC. 11 In addition, we illustrated the evidence of cross-recognition of human OGDC-E2 100-113 peptide (DEVVCEIETDKTSV), which is a distinct but related mitochondrial antigen recognized by some AMAs, by human PDC-E2 163-176 -reactive cloned T-cell lines established from PBC patients.…”