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Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide
Takamasa Oono, … , Michio Sata, Takehiko Sasazuki
Takamasa Oono, … , Michio Sata, Takehiko Sasazuki
Published December 1, 2001
Citation Information: J Clin Invest. 2001;108(11):1589-1596. https://doi.org/10.1172/JCI13256.
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Article

Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide

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Abstract

Organ-specific autoimmune diseases have been postulated to be the result of T cell response against organ-specific self-peptides bound to MHC molecules. Contrary to this paradigm, we report here that transgenic mice lacking MHC class I expression and expressing an MHC class II I-Ab molecule that presents only a single peptide (Eα52-68) spontaneously develops peripheral nervous system–specific autoimmune disease with many of the histopathological features found in experimental allergic neuritis. Reciprocal bone marrow chimeras produced using susceptible and resistant lines revealed that bone marrow–derived cells determined disease susceptibility. While the expression of the I-Ab–Eα52-68 complex in the periphery was readily detectable in both lines, its expression on thymic dendritic cells responsible for tolerance induction was markedly lower in the susceptible line than in the resistant line. Consistent with this, CD4+ T cells that can be activated by the I-Ab–Eα52-68 complex were found in the susceptible line, but not in the resistant line. Such CD4+ T cells conferred the disease to the resistant line by adoptive transfer, and administration of Ab specific for the I-Ab–Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-Ab–Eα52-68 complex, probably caused by incomplete negative thymocyte selection.

Authors

Takamasa Oono, Yoshinori Fukui, Sadahiko Masuko, Osamu Hashimoto, Takato Ueno, Terukazu Sanui, Ayumi Inayoshi, Mayuko Noda, Michio Sata, Takehiko Sasazuki

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Figure 3

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Phenotypic and functional analysis for self-reactivity of CD4+ T cells i...
Phenotypic and functional analysis for self-reactivity of CD4+ T cells in H3 TKO mice. (a) Expression of CD62L and CD44 on splenic CD4+ T cells from TKO, H3 TKO, and B2L TKO mice. The proportions of CD62L+CD44–, CD62L+CD44+, and CD62L–CD44+ cells are indicated. (b) Expression of CD25 on splenic CD4+ T cells from TKO, H3 TKO, and B2L TKO mice (upper panels), and comparison of proportions of CD4+CD25+ splenic T cells in these three lines (lower panel). TKO, n = 4; H3 TKO, n = 7; B2L TKO, n = 4. (c and d) After three or four rounds of stimulation of splenic CD4+ T cells from H3 TKO (filled bars) or B2L TKO (open bars) mice with irradiated B2H TKO spleen cells in the presence of cytokines, viable cells (1 × 105/well) were cultured with irradiated spleen cells (1 × 106/well) from B2H TKO or TKO mice in the presence or absence of YAe (20 μg/ml). The results represent the mean of [3H]thymidine incorporation of duplicate cultures (c), and mean and SD of cytokine production of triplicate cultures (d). For the experiments shown in c and d, three independent short-term-cultured CD4+ T cell lines were prepared from disease-affected H3 TKO mice. B2H, B2H TKO.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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