Thymic negative selection is functional in NOD mice (original) (raw)
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Journal of Autoimmunity, 2007
Recent data have suggested that non-obese diabetic (NOD) mice display a defect in negative thymic selection. Using mixed bone marrow chimeras, we demonstrate that the NOD allele of the diabetes susceptibility region 5 (Idd5) locus on chromosome 1, confers defective negative selection in response to endogenous superantigens (SAg) Mtv8 and Mtv9. We generated mixed bone marrow (BM) chimeras in which the donor cells of NOD and C3H or NOD.Idd5 b10 and C3H coexist and are similarly exposed to the Mtv8 and Mtv9 SAg. Under these conditions, SAgmediated deletion of Vb11 þ T cells is less efficient in chimeric mice reconstituted with NOD þ C3H BM, compared with chimeras reconstituted with NOD.Idd5 b10 þ C3H BM. Interestingly, the observed discrepancy was not T cell autonomous but was found to be mediated by a BM derived cellular subset, and under control of a gene(s) in the Idd5 region.
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).
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.
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.
T cell self-reactivity during thymic development dictates the timing of positive selection
eLife
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion ...
During T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3, we reexamined the block in positive selection observed in CD3 0 mice. We found that CD3 0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3 in positive selection is to quantitatively boost the signal for maximal generation of T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.
2021
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.
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.