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

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-A b 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-A b -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-A b -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-A b -Eα52-68 complex inhibited disease manifestation in the susceptible line. These results indicate that disease development involves systemic T cell reactivity to I-A b -Eα52-68 complex, probably caused by incomplete negative thymocyte selection.

Immunization with Glucose-6-Phosphate Isomerase Induces T Cell-Dependent Peripheral Polyarthritis in Genetically Unaltered Mice

“…In the K/B ϫ N model, arthritis is triggered by an autoimmune response against G6PI (5, 6). In the other model, autoimmune peripheral neuritis is triggered by autoreactive CD4 ϩ T cells that recognize I-A b / E␣ 52-68 (20). In this study, we describe a model where arthritis develops in genetically unmanipulated mice upon immunization with a ubiquitously expressed self-antigen.…”

“…Although it is unlikely that G6PI is a relevant autoantigen for any form of chronic inflammatory arthritis in patients, other ubiquitously expressed self-antigens may well be. Thus far, there has been a gap between the two transgenic models where either arthritis (5,6) or peripheral neuritis (20) are induced by systemic autoimmunity and a number of clinical situations where Abs against ubiquitously expressed Ags are highly specific for certain organ-specific autoimmune diseases. Prominent examples include the association of primary biliary cirrhosis with antimitochondrial Abs that recognize the E2 subunit of mitochondrial pyruvate dehydrogenase (39) and the association of antineutrophil cytoplasmic Abs targeting proteinase 3 with Wegener granulomatosis (40).…”

Impaired thymic negative selection causes autoimmune graft-versus-host disease

“…61 Similarly, transgenic mice H3-TKO develop CD4-dependent autoimmune neuritis due to impaired MHC class II-dependent thymic negative selection only in the absence of peripheral CD8 ϩ T cells. 26 Autoreactive T cells developed after impairing thymic negative selection by perinatal blockade of B7-1 and B7-2; these autoreactive T cells caused systemic autoimmune disease only after transfer into lethally irradiated or T-cell-deficient syngeneic hosts. 52 The interaction between autoreactive T cells and regulatory T cells in the generation of acute (syngeneic) GVHD thus may help to provide insight into the development of other autoimmune diseases.…”

“…[1][2][3][4][5] T cells with strong affinity for thymic MHC-peptide complexes are deleted in the thymic medulla via negative selection, which is mediated primarily by dendritic cells (DCs) and less efficiently by thymic medullary epithelial cells (MECs), [6][7][8][9][10][11][12] whereas positive selection is mediated by the thymic cortical epithelium. 1,[13][14][15][16][17] Several animal models of impaired thymic negative selection retain normal positive selection, including K14 mice that express MHC only on thymic cortical epithelium, 17,18 RelB-deficient mice lacking DCs and functional MECs, 19,20 H2-M-deficient mice, [21][22][23] transgenic mice expressing MHC linked to a single peptide, [24][25][26] and bone marrow (BM) chimeras lacking MHC expression on hematopoietic cells. 27,28 A common characteristic of all these models is the generation of a peripheral T-cell repertoire containing a large number of autoreactive T cells because of the impaired thymic negative selection.…”

Thymoproteasome Shapes Immunocompetent Repertoire of CD8+ T Cells

“…Based on these results, along with the structural analysis of TCR-MHC-peptide interactions, it is proposed that the specificity of TCR for peptides is not demanding during positive selection and that rather than positive selection, it is the subsequent negative selection that establishes the MHCrestriction specificity and the peptide specificity of peripheral T cells (Marrack and Kappler, 1997;Huseby et al, 2005;Dai et al, 2008;Huseby et al, 2008). However, those T cells generated in mice expressing single MHC-peptide ligands show markedly reduced cellularity and an unusual TCR repertoire that occasionally causes autoimmunity (Ignatowicz et al, 1996;Huseby et al, 2005;Oono et al, 2001). Thus, it is unclear whether the positive selection detectable in those single MHC-peptideexpressing mice represents positive selection occurring in the normal body.…”