Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells

Abstract

Intrathymic expression of tissue-specific self antigens may be involved in immunological tolerance and protection from autoimmune disease. We have analyzed the role of T-cell tolerance to proteolipid protein (PLP), the main protein of the myelin sheath, in susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Intrathymic expression of PLP was largely restricted to the shorter splice variant, DM20. Expression of DM20 by thymic epithelium was sufficient to confer T-cell tolerance to all epitopes of PLP in EAE-resistant C57BL/6 mice. In contrast, the major T-cell epitope in SJL/J mice was only encoded by the central nervous system-specific exon of PLP, but not by thymic DM20. Thus, lack of tolerance to this epitope offers an explanation for the exquisite susceptibility of SJL/J mice to EAE. As PLP expression in the human thymus is also restricted to the DM20 isoform, these findings have implications for selection of the autoimmune T-cell repertoire in multiple sclerosis.

An epitope from Acanthamoeba castellanii that cross-react with proteolipid protein 139-151-reactive T cells induces autoimmune encephalomyelitis in SJL mice

“…The lesser magnitude in the generation of PLP 139-151-specific T cells in ACA 83-95-immunized could lead to the generation of cross-reactive T cells both in periphery and locally within the CNS. Myelin antigens such as MBP and PLP can be expressed in thymus and peripheral lymphoid tissues and aberrant expression of PLP transcripts importantly DM20, an isoform of PLP lacking PLP 139-151 motif contribute to the endogenous generation of PLP 139-151 reactive T cells by escaping central tolerance (Anderson et al, 2000;Klein et al, 2000;Voskuhl, 1998). Furthermore, healthy humans including MS patients react to MBP or PLP suggestive of the existence of endogenous myelin reactive T cell repertoires and the resident dendritic cells and microglia can present antigens locally within CNS (Bailey et al, 2007;Pette et al, 1990;Wucherpfennig and Strominger, 1995).…”

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

“…Immunization of PLP À/À mice circumvented immunologic tolerance arising from the identity of human and murine PLP and its expression in lymphoid tissues (Voskuhl, 1998;Klein et al, 2000;Anderson and Kuchroo, 2003). Indeed, most of the PLP-reactive hybridomas were obtained from fusions using PLP À/À mice.…”

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

“…33 A similar mechanism has been proposed to explain the autoreactivity of SJL mice toward an epitope encoded by the DM20 splice variant of the proteolipid protein gene in induction of experimental allergic encephalomyelitis. 34 The association with the 8.1 ancestral HLA haplotype is likely to reflect a nonantigen specific dysregulation of the immune system, as this haplotype has been associated with susceptibility to different autoimmune diseases. 35 The TNFD marker belongs to the central region of HLA, which contains important candidate genes, notably lymphotoxin a and b and TNFa.…”