HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice

Durinovic‐Belló, Ivana; Steinle, A.; Ziegler, A. G.; Schendel, D. J.

doi:10.2337/diabetes.43.11.1318

Cited by 14 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next asked whether some of the TCRs of the GAD65responsive cells were shared between subjects. None of the GAD65-specific TCRs (both aand b-chain) was found in more than one subject, and none resembled those of previously published GAD-or islet-specific T cell clones (12,22,23). The CDR3 sequence of one GAD65-specific TCR b (CASSSGTVNTEAFF found in Infant 2) was previously described in an islet-infiltrating T cell clone of unknown Ag specificity (7), with different encoding TRBV genes (TRBV5-4 versus TRBV12-3).…”

Section: Tcr Sharingmentioning

confidence: 67%

High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells

Eugster

Lindner

Catani

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Autoreactive CD4(+) T cells are an essential feature of type 1 diabetes mellitus. We applied single-cell TCR α- and β-chain sequencing to peripheral blood GAD65-specific CD4(+) T cells, and TCR α-chain next-generation sequencing to bulk memory CD4(+) T cells to provide insight into TCR diversity in autoimmune diabetes mellitus. TCRs obtained for 1650 GAD65-specific CD4(+) T cells isolated from GAD65 proliferation assays and/or GAD65 557I tetramer staining in 6 patients and 10 islet autoantibody-positive children showed large diversity with 1003 different TCRs identified. TRAV and TRBV gene usage was broad, and the TRBV5.1 gene was most prominent within the GAD65 557I tetramer(+) cells. Limited overlap (<5%) was observed between TCRs of GAD65-proliferating and GAD65 557I tetramer(+) CD4(+) T cells. Few TCRs were repeatedly found in GAD65-specific cells at different time points from individual patients, and none was seen in more than one subject. However, single chains were often shared between patients and used in combination with different second chains. Next-generation sequencing revealed a wide frequency range (<0.00001-1.62%) of TCR α-chains corresponding to GAD65-specific T cells. The findings support minor selection of genes and TCRs for GAD65-specific T cells, but fail to provide strong support for TCR-targeted therapies.

show abstract

Section: Tcr Sharingmentioning

confidence: 67%

High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells

Eugster

Lindner

Catani

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The 4-1-E.2 clone was found to proliferate in the presence of islets, but there was no report of the antigen recognized by this clone. Interestingly, Durinovic-Bello et al reported the isolation of a T cell clone (K2.12) from a diabetic human with a TCR CDR3β motif of SRLGNQ (15). It remains to be seen if clones 4-1-E.2 and K2.12 can recognize hsp60 peptide p277.…”

Section: Discussionmentioning

confidence: 99%

“…The C7, N1, N26 and other clones that recognize the p277 peptide of human hsp60 were diabetogenic and could vaccinate NOD mice against developing diabetes (2). We also studied the N4 clone that reacts to Mycobacterium tuberculosis hsp65 but not to human hsp60, and is neither diabetogenic nor (14) and that of human clone K2.12 is taken from Duranovic-Bellow et al (15). vaccinates against diabetes (2), and an unrelated anti-OVA line.…”

Section: Tcr Usage In Other Nod T Cell Linesmentioning

confidence: 99%

“…Note that 4-1-E.2, like C9, expresses the V β 12 and J β 2.5 genes, and has a CDR3β region sequence similar in part to that of C9: C9-LGGNQD; 4-1-E.2-LGNQD. Table 1 also includes the published sequence of the CDR3β chain of a human T cell clone reactive to β cells (15). The human clone K2.12 appears to express a CDR3 sequence with the LGNQ motif that differs by the lack of a G from the LGGNQ amino acid sequence of C9.…”

Section: Tcr Usage In Other Nod T Cell Linesmentioning

confidence: 99%

See 1 more Smart Citation

A shared TCR CDR3 sequence in NOD mouse autoimmune diabetes

Tikochinski

Elias²,

Steeg³

et al. 1999

International Immunology

View full text Add to dashboard Cite

T cells involved in autoimmune diseases have been characterized by the genetic elements used to construct their autoimmune TCR. In the present study, we sequenced the alpha and beta chains of the TCR expressed by a CD4(+) T cell clone, C9, functional in NOD mouse diabetes. Clone C9 can adoptively transfer diabetes or, when attenuated, C9 can be used to vaccinate NOD mice against diabetes. Clone C9 recognizes a peptide epitope (p277) of the 60 kDa heat shock protein (hsp60) molecule. We now report that the C9 TCR beta chain features a CDR3 peptide sequence that is prevalent among NOD mice. This CDR3 element is detectable by 2 weeks of age in the thymus, and later in the spleen and in the autoimmune insulitis. Thus, a TCR CDR3beta sequence appears to be a common idiotope associated with mouse diabetes.

show abstract

“…The first two sets of controls were compared with 103 CD3 V beta/D/J beta TCR sequences from six people with CD . The controls were also compared with 68 CD3 V beta TCR sequences from eight people with T1DM .…”

Section: Methodsmentioning

confidence: 99%

Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

Root‐Bernstein

2016

BioEssays

View full text Add to dashboard Cite

I propose a T-cell receptor (TcR)-based mechanism by which immunity mediates both "genetic self" and "microbial self" thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross-reactivity with "self," resulting in selection for a TcR repertoire mimicking "genetic self." Second, evolution has selected for a "microbial self" that mimics "genetic self" so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR-microbiome mimicry "holoimmunity" to denote immune tolerance to the "holobiont self." Logically, microbiome-host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross-react with host antigens producing "holoautoimmunity."

show abstract

HLA-DQ-restricted, islet-specific T-cell clones of a type I diabetic patient. T-cell receptor sequence similarities to insulitis-inducing T-cells of nonobese diabetic mice

Cited by 14 publications

References 0 publications

High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells

High Diversity in the TCR Repertoire of GAD65 Autoantigen-Specific Human CD4+ T Cells

A shared TCR CDR3 sequence in NOD mouse autoimmune diabetes

Autoimmunity and the microbiome: T‐cell receptor mimicry of “self” and microbial antigens mediates self tolerance in holobionts

Contact Info

Product

Resources

About