TCR repertoire to proteolipid protein (PLP) in multiple sclerosis (MS): homologies between PLP-specific T cells and MS-associated T cells in TCR junctional sequences

Abstract

In the pathogenesis of multiple sclerosis (MS), autoimmune T cells reactive with proteolipid protein (PLP) may play a crucial role. We determined 23 TCR beta-chain sequences of limiting dilution T cel lines (TCL) selected against a synthetic peptide, PLP 95-116, 105-124 or 139-155, from the peripheral blood of three Japanese MS patients with the DR2,w15 haplotype (TI, SK and OK). Fourteen sequences were originated from TI, seven from SK and two from OK. The PLP-reactive TCL utilized various Vbeta and Jbeta gene segments, but there was significant bias in the Vbeta and Jbeta usage. Overutilization of the Vbeta2 family and dominant usage of the Jbeta2.5 subfamily was seen in PLP 105-124-reactive and 95-116-reactive TCL respectively. More remarkably, a majority of the TCL were found to express beta-chain CDR3 motifs that appear to be unique to MS brain infiltrates. In contrast, these motifs were only rarely seen in control TCR sequences from peripheral blood or from a TCL selected against tetanus toxoid. In several cases, the betaCDR3 homologies between the PLP-reactive T cells and MS brain T cells were extensive, owing to the shared motifs in combination with the surrounding amino acid identities. These results indicate that PLP-specific T cells may be involved in the immunopathology of MS.