T-cell lines reactive to an immunodominant epitope of the tyrosine phosphatase-like autoantigen IA-2 in type 1 diabetes.

Hawkes, C. J.; Schloot, Nanette C.; Marks, J.D.; Willemen, Sabine J. M.; Drijfhout, Jan W.; Mayer, Erik; Christie, Michael R.; Roep, Bart O.

doi:10.2337/diabetes.49.3.356

Cited by 64 publications

(43 citation statements)

References 43 publications

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“…In contrast, the T cell targets of human T1D have been identified only from the analysis of peripheral T cells, mostly because of the limited availability of human pancreatic tissue. Autoreactive T cells were identified in vitro by expansion against insulin, GAD, I-A2, IGRP (7)(8)(9)(10), and ex vivo by positive staining with self-peptide-MHC tetramers (11,12). Although there are no data on the specificity of intrapancreatic T cells in human T1D, phenotypic analysis of infiltrating lymphocytes have shown that the human pancreas is infiltrated with both CD8 + and CD4 + T cells (13)(14)(15)(16)(17)(18).…”

Section: T Ype 1 Diabetes (T1d) Is An Autoimmune Disease Defined By Tmentioning

confidence: 99%

“…Studies published so far have described the repertoire of human T cells isolated from patients' PBMCs that have been expanded in vitro in front of cognate autoantigens (7)(8)(9)(10), but this does not reflect their in vivo distribution or frequency. One such study reported the repertoire of T cells from the PLN of diabetic donors expanded in vitro with insulin, but none of the clones could be found in the spleen of the same donor (21).…”

Section: Cdr3 Length (Aa)mentioning

confidence: 99%

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TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Codina-Busqueta

Scholz

Torres

et al. 2011

The Journal of Immunology

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Autoreactive T cells, responsible for the destruction of pancreatic β cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient’s peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR β-chain variable expansions were detected for Vβ1, Vβ7, Vβ11, Vβ17, and Vβ22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vβ22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR β-chain variable repertoire. The same Vβ22 TCR was detected in the patient’s PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vβ22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient’s spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells.

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Section: T Ype 1 Diabetes (T1d) Is An Autoimmune Disease Defined By Tmentioning

confidence: 99%

Section: Cdr3 Length (Aa)mentioning

confidence: 99%

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Codina-Busqueta

Scholz

Torres

et al. 2011

The Journal of Immunology

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“…umbers of autoaggressive CD4 and CD8 lymphocytes are thought to directly correlate with the incidence and severity of type 1 diabetes and other autoimmune disorders (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Indeed, increased numbers are usually present in mice with more severe disease (11)(12)(13), but the situation in humans is still unclear, and lymphocytes with specificity for islet antigens are not always consistently detectable in peripheral blood of prediabetic or diabetic individuals (unpublished, 4th International Diabetes Workshop, November 1999, Fiuggi, Rome).…”

mentioning

confidence: 99%

Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain

et al. 2001

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In comparing the incidence of virally induced type 1 diabetes in F 1 crosses of RIP-LCMV mice to three different mouse strains identical at the major histocompatibility complex H-2D b locus, we surprisingly found that disease development was reduced by 80% in F 1 crosses to the SV129 genetic background and by 60% after eight backcrosses to the original C57BL/6 RIP-LCMV mice. In this model, diabetes is strongly dependent on a virally induced H-2D b -restricted cytotoxic T-cell (CTL) response. Importantly, numbers and effector functions of autoaggressive CD4 and CD8 lymphocytes were not decreased in the protected mice, and CTLs were still able to kill syngeneic islet cells in vitro with equal efficacy compared with CTLs from the original RIP-LCMV strain. Furthermore, CTLs were able to extravasate into islets in vivo, and no evidence for induction of regulatory cells was observed. However, regeneration of ␤-cells in islets under "attack" occurred only in the protected SV129-crossed animals, whereas it was not evident at any time in any mice that developed diabetes. Thus, genetic factors can "override" the diabetogenic potential of high numbers of autoaggressive lymphocytes through, for example, increased islet regeneration. This finding has important implications for interpreting numbers and pathogenicity of autoreactive lymphocytes in prediabetic patients of genetically diverse backgrounds.

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“…Three independent T-cell clones were previously isolated from two newly diagnosed Type I diabetic patients and a prediabetic subject 4 years before the clinical manifestation of the disease [10,11,12]. Clone 1C6 is directed against beta-cell membrane protein, clone PM1-11 is directed against GAD65 (Diamyd, Stockholm, Sweden) and clone KD9665 is directed against IA-2 (kindly provided by Dr M.R.…”

Section: Methodsmentioning

confidence: 99%

“…T-cells were co-cultured with irradiated autologous or HLA-DR-matched PBMC in culture medium (RPMI 1640, 10% human pooled serum) or stimulated with IL-2, PHA or sub-maximal concentrations of specific autoantigens and synthetic peptide epitopes thereof [10,11,12]. Proteases were added in a dose range from 3.1-100 µg/ml.…”

Section: Generation Of Immature Dendritic Cellsmentioning

confidence: 99%

Modulation of autoimmunity to beta-cell antigens by proteases

et al. 2002

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Aims/hypothesis. Proteases are used in therapy for autoimmune diseases yet the mechanism of their action remains to be determined. We studied the immunological basis of protease therapy in the context of Type I (insulin-dependent) diabetes mellitus. Methods. We studied the effects of proteases (trypsin, papain, chymotrypsin, bromelain) on immune reactivity of a series of autoreactive T-cell clones from prediabetic subjects and patients with a recent onset of Type I diabetes and specific to the autoantigens GAD65, IA-2 and insulin-secretory granule protein.Results. Cell surface expression of adhesion, co-stimulatory and homing molecules on both antigen-presenting cells and T cells was changed after protease treatment. Cytokine analyses showed a selective inhibition of proinflammatory (Th-1) but not Th-2 cytokine production. Autoreactive T-cell proliferation was inhibited at pharmacological serum concentrations, whereas non-specific proliferation to phytohaemagglutinin was not affected at these concentrations. Preincubation experiments on T cells and antigen-presenting cells separately showed that this effect was mediated by APCs, but not T-cells. Conclusion/interpretation. Proteases have pleiotropic immunological effects supporting an immunomodulatory potential for the intervention of chronic inflammatory diseases and Th-1 mediated oedema formation. [Diabetologia (2002) 45:686-692]

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T-cell lines reactive to an immunodominant epitope of the tyrosine phosphatase-like autoantigen IA-2 in type 1 diabetes.

Cited by 64 publications

References 43 publications

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain

Modulation of autoimmunity to beta-cell antigens by proteases

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