High Frequency of Autoreactive Myelin Proteolipid Protein–Specific T Cells in the Periphery of Naive Mice

Abstract

The autoreactive T cells that escape central tolerance and form the peripheral self-reactive repertoire determine both susceptibility to autoimmune disease and the epitope dominance of a specific autoantigen. SJL (H-2s) mice are highly susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) with myelin proteolipid protein (PLP). The two major encephalitogenic epitopes of PLP (PLP 139–151 and PLP 178–191) bind to IAs with similar affinity; however, the immune response to the PLP 139–151 epitope is always dominant. The immunodominance of the PLP 139–151 epitope in SJL mice appears to be due to the presence of expanded numbers of T cells (frequency of 1/20,000 CD4+ cells) reactive to PLP 139–151 in the peripheral repertoire of naive mice. Neither the PLP autoantigen nor infectious environmental agents appear to be responsible for this expanded repertoire, as endogenous PLP 139–151 reactivity is found in both PLP-deficient and germ-free mice. The high frequency of PLP 139–151-reactive T cells in SJL mice is partly due to lack of thymic deletion to PLP 139–151, as the DM20 isoform of PLP (which lacks residues 116–150) is more abundantly expressed in the thymus than full-length PLP. Reexpression of PLP 139–151 in the embryonic thymus results in a significant reduction of PLP 139–151-reactive precursors in naive mice. Thus, escape from central tolerance, combined with peripheral expansion by cross-reactive antigen(s), appears to be responsible for the high frequency of PLP 139–151-reactive T cells.

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).…”

Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide

“…However, for lymphocytes that escaped central tolerance, peripheral tolerance mechanisms would operate to protect against destructive auto-immunity through active suppression by regulatory cells or via a mechanism called clonal ignorance [37,38]. Of particular interest, prior studies have revealed that central tolerance is operative for so-called "sequestered" antigens such as PLP [24,25]. In fact, a splice variant of PLP is promiscuously expressed in the thymus and would play some role in shaping the T cell repertoire.…”

“…Moreover, it has been proven that a splice variant of myelin proteolipid protein (PLP), an encephalitogenic antigen causing EAE, is promiscuously expressed in the thymus and plays a role in shaping the autoimmune T cell repertoire [24,25]. Given this information together with our experimental data, an attractive hypothesis was that self-tolerance to P0 might be defective in P0-deficient mice owing to a lower expression of P0 in the thymus, a place for establishing self-tolerance to P0.…”

“…Recent studies demonstrate that a number of autoantigens, including those that were believed to be secluded from the immune system, are actually expressed in the thymus [19][20][21][22][23][24][25][26][27]. Furthermore, experiments have proven that such a promiscuous expression of autoantigen would contribute to eliminating pathogenic autoimmune T cells from the T cell repertoire [24,25]. We found that the P0 gene is also transcribed in the thymus, but the transcription level is reduced in P0 +/-mice as compared to wild-type mice.…”

Cell-based gene therapy experiments in murine experimental autoimmune encephalomyelitis

“…This appears to be due to the high frequency of PLP 139-151-reactive T cells observed in these mice. 54 In this article we now examine a second epitope, MBP 89-101, in order to determine whether our protocol is PLPspecific or is more generally applicable. We show that by inducing disease with MBP protein (instead of MSCH) we can ameliorate disease using transduced fibroblasts secreting either the MBP 89-101 or PLP 139-151 epitope.…”