Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice

Greeley, Siri Atma W.; Moore, Daniel J.; Noorchashm, Hooman; Noto, Lauren E.; Rostami, Susan; Schlachterman, Alexander; Song, Howard K.; Koeberlein, Brigitte; Barker, Clyde F.; Naji, Ali

doi:10.4049/jimmunol.167.8.4351

Cited by 62 publications

(72 citation statements)

References 36 publications

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“…Interestingly, although NOD mice with functionally incompetent B cells are diabetes-resistant, they still harbor pathogenic T cells (6,70). This observation indirectly implicates DC in the initial selection of diabetogenic T cells, but suggests that the subsequent expansion and/or maintenance of autoreactive T cells relies heavily on the B cell compartment.…”

Section: Discussionmentioning

confidence: 98%

Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice

Marleau

Summers

Singh

2008

The Journal of Immunology

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Despite the pivotal role of dendritic cells (DC) in shaping immunity, little is known about their functionality in type 1 diabetes. Moreover, due to the paucity of DC in vivo, functional studies have relied largely upon in vitro-expanded cells to elucidate type 1 diabetes-associated functional abnormalities. In this study, we provide a comprehensive analysis of the functional capabilities of in vivo-derived DC subsets from NOD mice by comparing DC to other NOD APC types and to DC from autoimmune-resistant strains. NOD DC closely resemble those from nonautoimmune strains with respect to costimulation and cytokine production. The exception is the CD8α+CD11b−DC subset which is numerically reduced in NOD spleens, but not in the pancreatic lymph nodes, while DC from both tissues produce little IL-12 in this strain. This defect results in unusual deferral toward macrophage-derived IL-12 in NOD mice; NOD macrophages produce aberrantly high IL-12 levels that can overcompensate for the DC defect in Th1 polarization. APC subset use for autoantigen presentation also differs in NOD mice. NOD B cells overshadow DC at activating islet-reactive T cells, whereas DC and B cells in NOD-resistant mice are functionally comparable. Differential involvement of APC subsets in T cell activation and tolerance induction may prove to be a crucial factor in the selection and expansion of autoreactive T cells.

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Section: Discussionmentioning

confidence: 98%

Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice

Marleau

Summers

Singh

2008

The Journal of Immunology

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“…Studies in µMT -/-mice that had been backcrossed 8 times [27] or 10 times to NOD mice [34] had shown very little insu-litis at 12 weeks [27,34] whereas insulitis occurred as early as 8 weeks in NOD.µMT -/-backcrossed 14 generations to NOD mice [35], even though overall, insulitis is reduced. This indicates that B cells may not be absolutely required for the initiation stage of the autoimmune process but they can traffic to the islets and facilitate the development of diabetes.…”

Section: B Cells In Autoimmune Diabetes In the Nod Mousementioning

confidence: 99%

“…Their experiments indicated, using anti-CD3 as a stimulus, that B cell costimulation was required for effective CD4 T cell activation. Costimulation by B cells in the pancreatic lymph nodes is important [34] in addition to the activation of T cells by B cells within the islets [70].…”

Section: B Cell Characteristics In Nod Micementioning

confidence: 99%

B Cells in Autoimmune Diabetes

Wong

Liu²

2005

Rev Diab Stud

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■ AbstractAutoantibodies have been used as good markers for the prediction of future development of type 1 diabetes mellitus (T1DM), but are not thought to be pathogenic in this disease. The role of B cells that produce autoantibodies in the pathogenesis of human T1DM is largely unknown. In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, it has been shown that B cells may contribute multifariously to the pathogenesis of the disease. Some aspects of deficiencies of B cell tolerance may lead to the circulation of autoreactive B cells. In addition, the antigenpresenting function of autoantigen specific B cells is likely to be particularly important, and autoantibodies are also considered to play a critical role. This review discusses the possible aspects of B cells involved in the development of autoimmune diabetes.

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“…Others have demonstrated generally impaired lymph node T cell activation in congenitally B cell-deficient NOD mice, suggesting a critical need for B cell costimulatory signals within these microenvironments (48). Therefore, the effects of B cell depletion on T cell numbers, phenotypes, and proliferative capacity was assessed in NOD mice given CD20 or control mAb at 5 wk of age.…”

Section: B Cell Depletion Reduces T Cell Proliferation But Does Notmentioning

confidence: 99%

B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in FcγR Effector Functions

Xiu

Wong

Bouaziz

et al. 2008

The Journal of Immunology

205

192

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NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by ∼95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcγRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 μg) in NOD mice, FcγRIII and FcγRIV compensated for inadequate FcγRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcγR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.

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Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice

Cited by 62 publications

References 36 publications

Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice

Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice

B Cells in Autoimmune Diabetes

B Lymphocyte Depletion by CD20 Monoclonal Antibody Prevents Diabetes in Nonobese Diabetic Mice despite Isotype-Specific Differences in FcγR Effector Functions

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