The NOD allele of the Idd5 locus on chromosome 1 mediates a non-cell-autonomous defect in negative selection of T cells (original) (raw)
Related papers
2007
Background: T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain Results: Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. Conclusion: The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.
Thymic negative selection is functional in NOD mice
Journal of Experimental Medicine, 2012
Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences /-lineage decisions promoted by early expression of tg -TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg -TCRs behave like -TCRs and commit a large fraction of DNs toward the -lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, -TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD -TCR signalosomes. Therefore, NOD genetic variation influences /-lineage decisions when the -TCR heterodimer is prematurely expressed, but not the process of negative selection.
European Journal of Immunology, 1993
The effect of bone marrow and thymus chimerism between non-obese diabetic (NOD) and NODE transgenic mice, on the expression and prevention of diabetes The non-obese diabetic (NOD) mouse is an established animal model of the autoimmune disease, insulin-dependent diabetes mellitus (IDDM). The NODE mouse is a transgenic mouse which expresses the I-E molecule (absent in NOD mice). Expression of I-E protects these mice from both insulitis and IDDM. We have investigated the possible mechanisms of this protection by constructing bone marrow, and combined bone marrow and thymus chimeras between NOD and NODE mice. Our data suggest that thymic epithelium may play no direct role in either protection against, or promotion of, IDDM. Protection from diabetes is provided either by NODE donor bone marrow or NODE recipient non-thymic radioresistant cells. The means by which protection may be achieved in this system are discussed.
Diabetes, 2012
Prevention of autoimmunity requires the elimination of selfreactive T cells during their development in the thymus and maturation in the periphery. Transgenic NOD mice that overexpress islet-specific glucose 6 phosphatase catalytic subunitrelated protein (IGRP) in antigen-presenting cells (NOD-IGRP mice) have no IGRP-specific T cells. To study the relative contribution of central and peripheral tolerance mechanisms to deletion of antigen-specific T cells, we crossed NOD-IGRP mice to highly diabetogenic IGRP 206-214 T-cell receptor transgenic mice (NOD8.3 mice) and studied the frequency and function of IGRP-specific T cells in the thymus and periphery. Peripheral tolerance was extremely efficient and completely protected NOD-IGRP/NOD8.3 mice from diabetes. Peripheral tolerance was characterized by activation of T cells in peripheral lymphoid tissue where IGRP was expressed followed by activation-induced cell death. Thymectomy showed that thymic output of IGRP-specific transgenic T cells compensated for peripheral deletion to maintain peripheral T-cell numbers. Central tolerance was undetectable until 10 weeks and complete by 15 weeks. These in vivo data indicate that peripheral tolerance alone can protect NOD8.3 mice from autoimmune diabetes and that profound changes in T-cell repertoire can follow subtle changes in thymic antigen presentation. Diabetes 61:425-435, 2012 B y exposing developing thymocytes to self-antigens, the thymus purges the majority of autoreactive T cells by a process called negative selection. Experiments in animal models have demonstrated that stromal medullary thymic epithelial cells (ECs) and bone marrow-derived thymic dendritic cells (DCs) play an important role by expressing self-antigens to mediate thymocyte negative selection (1). Many, but not all, tissue-specific antigens that are expressed in medullary thymic ECs are controlled by the autoimmune regulator (AIRE) transcription factor (2-5). Thymic DCs have been shown to broaden the spectrum of self-antigens presented to developing T cells either by expressing self-antigens or presenting self-antigens after capturing them from medullary ECs (6).
European Journal of Immunology, 2008
Adhesion and Degranulation Promoting Adapter protein (ADAP), a positive regulator of T cell receptor (TCR) signaling, is required for thymocyte development and T cell homeostasis. To investigate the role of ADAP in a T cell-driven autoimmune response, we generated ADAPdeficient, BDC2.5 TCR transgenic, diabetes-prone (C57Bl/6) mice (BDC/B6). We observed a striking enhancement of diabetes incidence in ADAP-deficient mice, both in animals homozygous for I-A g7 , and in mice carrying one I-A b allele (BDC/B6 g7/b ). Increased disease correlates with significantly reduced numbers of pathologic CD4 + T cells in the mice. Consistent with a state of functional lymphopenia in ADAP-deficient BDC/B6 g7/b mice, T cells display increased homeostatic proliferation. Transfer of syngeneic lymphocytes or T cells both blocks ADAPdependent diabetes and relieves exaggerated homeostatic T cell proliferation observed in ADAPdeficient mice. Marked attenuation in cellularity of the CD4 + single-positive (SP) thymocyte compartment in ADAP-deficient BDC/B6 g7/b animals suggests a mechanism for induction of the lymphopenia. We conclude that inefficient positive selection in ADAP deficiency results in lymphopenia that leads to enhanced autoimmune diabetes in the BDC/B6 g7/b model. Our findings support the notion that ineffective thymic T cell output can be a powerful causative factor in lymphopenia-driven autoimmune diabetes.
Idd9/11 Genetic Locus Regulates Diabetogenic Activity of CD4 T-Cells in Nonobese Diabetic (NOD) Mice
Diabetes, 2008
OBJECTIVE-Although the H2 g7 major histocompatibility complex (MHC) provides the primary pathogenic component, the development of T-cell-mediated autoimmune type 1 diabetes in NOD mice also requires contributions from other susceptibility (Idd) genes. Despite sharing the H2 g7 MHC, the closely NODrelated NOR strain remains type 1 diabetes resistant because of contributions of protective Idd5.2, Idd9/11, and Idd13 region alleles. To aid their eventual identification, we evaluated cell types in which non-MHC Idd resistance genes in NOR mice exert disease-protective effects.
The Journal of Immunology, 2008
When expressed in NOD, but not C57BL/6 (B6) genetic background mice, the common class I variants encoded by the H2 g7 MHC haplotype aberrantly lose the ability to mediate the thymic deletion of autoreactive CD8 ؉ T cells contributing to type 1 diabetes (T1D). This indicated some subset of the T1D susceptibility (Idd) genes located outside the MHC of NOD mice interactively impair the negative selection of diabetogenic CD8 ؉ T cells. In this study, using both linkage and congenic strain analyses, we demonstrate contributions from a polymorphic gene(s) in the previously described Idd7 locus on the proximal portion of Chromosome 7 predominantly, but not exclusively, determines the extent to which H2 g7 class I molecules can mediate the thymic deletion of diabetogenic CD8 ؉ T cells as illustrated using the AI4 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the AI4 clonotypic TCR ␣-chain on developing thymocytes in B6.H2 g7 and NOD background mice. This expression difference likely lowers levels of the clonotypic AI4 TCR in NOD, but not B6.H2 g7 thymocytes, below the threshold presumably necessary to induce a signaling response sufficient to trigger negative selection upon Ag engagement. These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients.
2018
In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic β-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8+ T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant is likely an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-med...
Frontiers in immunology, 2018
Stable mixed hematopoietic chimerism is a robust method for inducing donor-specific tolerance with the potential to prevent rejection of donor islets in recipients with autoimmune type-1 diabetes. However, with reduced intensity conditioning, fully allogeneic chimerism in a tolerance resistant autoimmune-prone non-obese diabetic (NOD) recipient has rarely been successful. In this setting, successful multilineage chimerism has required either partial major histocompatability complex matching, mega doses of bone marrow, or conditioning approaches that are not currently clinically feasible. Irradiation free protocols with moderate bone marrow doses have not generated full tolerance; donor skin grafts were rejected. We tested whether more efficient recipient T cell depletion would generate a more robust tolerance. We show that a combination of donor-specific transfusion-cyclophosphamide and multiple T cell depleting antibodies could induce stable high levels of fully allogeneic chimeris...
Bim deficiency protects NOD mice from diabetes by diverting thymocytes to regulatory T cells
Diabetes, 2015
Because regulatory T (Treg) cell development can be induced by the same agonist self antigens that induce negative selection, perturbation of apoptosis will impact both negative selection and Treg cell development. But how the processes of thymocyte deletion versus Treg cell differentiation bifurcate and their relative importance for tolerance has not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, Bim, in the non-obese diabetic (NOD) mouse model of autoimmune diabetes.