The Role of CD4 . CD8 T Cells in IDDM

Wong, F. Susan; Ca, Janeway

doi:10.1006/jaut.1999.0322

Cited by 64 publications

(56 citation statements)

References 76 publications

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“…ϩ T-cells have recently emerged as crucial actors in the pathogenesis of type 1 diabetes in the NOD mouse (1,2). Three different CD8 ϩ pathogenic clones specific for proinsulin B15-23 (3), islet-specific glucose-6-phosphatase catalytic subunitrelated protein (IGRP) 206 -214 (4), and dystrophia myotonica kinase 138 -146 (5) have been described.…”

Section: D8mentioning

confidence: 99%

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

et al. 2008

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OBJECTIVE-Islet-reactive CD8ϩ T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown. RESEARCH DESIGN AND METHODS-We took advantage of a recently validated islet-specific CD8ϩ T-cell ␥-interferon enzyme-linked immunospot (ISL8Spot) assay to follow responses against preproinsulin (PPI), GAD, insulinoma-associated protein 2 (IA-2), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2 ϩ adult type 1 diabetic patients close to diagnosis and at a second time point 7-16 months later. RESULTS-CD8ϩ T-cell reactivities were less frequent at follow-up, as 28.6% of responses tested positive at type 1 diabetes diagnosis vs. 13.2% after a median of 11 months (P ϭ 0.003). While GAD and IA-2 autoantibody (aAb) titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes by ISL8Spot decreased from 60 -67 to 20% (P Ͻ 0.02). The previously subdominant IA-2 206 -214 and IGRP [265][266][267][268][269][270][271][272][273] peptides were newly targeted, thus becoming the immunodominant epitopes. CONCLUSIONS-Shifts both in frequency and in immunodominance of CD8ϩ T-cell responses occur more rapidly than do changes in aAb titers. These different kinetics may suggest complementary clinical applications for T-cell and aAb measurements. Diabetes 57:1312-1320, 2008

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Section: D8mentioning

confidence: 99%

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

et al. 2008

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“…Both CD4 ϩ and CD8 ϩ T cells comprise the effector arm, with underlying functional defects in bone marrow-derived APC (e.g., macrophages, dendritic cells, and B lymphocytes) serving as essential components in the selection and activation of the autoimmune repertoire (2). Although the exact cause of this disease is poorly understood, numerous reports have made strong correlations between type 1 diabetes and a Th1-biased immunophenotype (3,4).…”

mentioning

confidence: 99%

Systemic Overexpression of IL-10 Induces CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic Mice in a Dose-Dependent Fashion

Goudy

Burkhardt

Wasserfall

et al. 2003

The Journal of Immunology

124

131

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Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (104, 106, 108, and 109 infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (109 IU), or saline. Transduction with rAAV-IL-10 at 109 IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 108 IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.

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“…These findings have recently been confirmed using the PPI [15][16][17][18][19][20][21][22][23][24] clone and an additional HLA-A2-restricted PPI clone, PPI [3][4][5][6][7][8][9][10][11] [106]. These clones killed beta-cells by requiring a direct interaction via MHC class I and utilizing perforin and granzymes.…”

Section: Effector Mechanisms Utilized By Human Auto-reactive Ctlsmentioning

confidence: 83%

“…+ and CD8 + T cell clones results in accelerated diabetes on the NOD background [3,4]. However, in non-transgenic mice, both CD8 + and CD4 + T cells are essential for the development of spontaneous diabetes as a deficiency of either prevents the development of insulitis and diabetes [4].…”

Section: T Lymphocytes Destroy Beta-cellsmentioning

confidence: 99%

“…Recent X-ray crystallography revealed the interaction between HLA-A2/PPI [15][16][17][18][19][20][21][22][23] peptide/TCR [55]. Most attempts to define CD8 + T cell responses have focused on HLA A2, but recently an HLA A24-restricted epitope derived from proinsulin, PPI [3][4][5][6][7][8][9][10][11] , has been identified using a similar peptide elution approach [56].…”

Section: Antigen Specificity Of Autoreactive T Cells In Human Type 1 mentioning

confidence: 99%

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Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

et al. 2012

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Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4 + T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8 + T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of the disease. The majority of our knowledge of these pathogenic processes is derived from the NOD mouse model, although some processes are mirrored in the human disease. However, more work is required to translate the data from the NOD mouse to our understanding of human diabetes pathogenesis. New technology, especially MHC tetramers and modern imaging, will enhance our understanding of the pathogenic mechanisms.

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The Role of CD4 . CD8 T Cells in IDDM

Cited by 64 publications

References 76 publications

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

Systemic Overexpression of IL-10 Induces CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic Mice in a Dose-Dependent Fashion

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

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