Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity

Stratmann, Thomas; Martín‐Orozco, Natalia; Mallet-Designe, Valérie; Poirot, Laurent; McGavern, Dorian B.; Losyev, Grigoriy; Dobbs, Cathleen M.; Oldstone, Michael B. A.; Yoshida, Kenji; Kikutani, Hitoshi; Mathis, Diane; Benoist, Christophe; Haskins, Kathryn; Teyton, Luc

doi:10.1172/jci200318337

Cited by 53 publications

(55 citation statements)

References 68 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with previous studies suggesting that susceptible MHC alleles are responsible for selection of autoreactive T cells (18,29). NOD.DR3 mice do not respond spontaneously to myosin and produce very low levels of anti-cardiac myosin antibodies.…”

Section: Discussionsupporting

confidence: 93%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggest that NOD.DQ8 may harbor autoreative cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

show abstract

Section: Discussionsupporting

confidence: 93%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…To extend these observations, we also assessed Erk1/2 phosphorylation in T cells from BDC2.5 TCR transgenic mice, stimulated with whole splenocytes loaded with mimotope agonist peptide (26). The response was more persistent than that elicited by antibody-mediated cross-linking, yet the same Treg/Tconv difference was present with this more physiological mode of activation ( Fig.…”

Section: Significancementioning

confidence: 97%

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Yan

Farache

Mingueneau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

show abstract

“…might be expected from their role in selecting T-cells and presenting self-antigens. In the NOD mouse, the H2 g7 MHC alleles associated to type 1 diabetes are sufficient to select an autoreactive repertoire (48). More puzzling is the additional contribution of DQB1*0302 to further progression.…”

Section: Discussionmentioning

confidence: 99%

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

et al. 2008

Self Cite

View full text Add to dashboard Cite

the DPT-1 Study Group OBJECTIVE-The unfolding of type 1 diabetes involves a number of steps: defective immunological tolerance, priming of anti-islet autoimmunity, and destruction of insulin-producing ␤-cells. A number of genetic loci contribute to susceptibility to type 1 diabetes, but it is unclear which stages of the disease are influenced by the different loci. Here, we analyzed the frequency of type 1 diabetes-risk alleles among individuals from the Diabetes Prevention Trial-Type 1 (DPT-1) clinical trial, which tested a preventive effect of insulin in at-risk relatives of diabetic individuals, all of which presented with autoimmune manifestations but only one-third of which eventually progressed to diabetes. RESEARCH DESIGN AND METHODS-In this study, 708individuals randomized into DPT-1 were genotyped for 37 single nucleotide polymorphisms in diabetes susceptibility loci.RESULTS-Susceptibility alleles at loci expected to influence immunoregulation (PTPN22, CTLA4, and IL2RA) did not differ between progressors and nonprogressors but were elevated in both groups relative to general population frequencies, as was the INS promoter variant. In contrast, HLA DQB1*0302 and DQB1*0301 differed significantly in progressors versus nonprogressors (DQB*0302, 42.6 vs. 34.7%, P ϭ 0.0047; DQB*0301, 8.6 vs. 14.3%, P ϭ 0.0026). Multivariate analysis of the factors contributing to progression demonstrated that initial titers of anti-insulin autoantibodies (IAAs) could account for some (P ϭ 0.0016) but not all of this effect on progression (P ϭ 0.00038 for the independent effect of the number of DQB*0302 alleles). The INS-23 genotype was most strongly associated with anti-IAAs (median IAA levels in TT individuals, 60 nU/ml; AT, 121; and AA, 192; P ϭ 0.000037) and only suggestively to the outcome of oral insulin administration.CONCLUSIONS-With the exception of HLA, most susceptibility loci tested condition the risk of autoimmunity rather than the risk of failed immunoregulation that results in islet destruction. Future clinical trials might consider genotyping INS-23 in addition to HLA alleles as disease/treatment response modifier.

show abstract

Susceptible MHC alleles, not background genes, select an autoimmune T cell reactivity

Cited by 53 publications

References 68 publications

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

Contact Info

Product

Resources

About