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*
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA 19104; and
Division of Nephrology, London Health Sciences Centre, London, Ontario, Canada
B cell-deficient nonobese diabetic (NOD) mice are protected from the development of spontaneous autoimmune diabetes, suggesting a requisite role for Ag presentation by B lymphocytes for the activation of a diabetogenic T cell repertoire. This study specifically examines the importance of B cell-mediated MHC class II Ag presentation as a regulator of peripheral T cell tolerance to islet ß cells. We describe the construction of NOD mice with an I-Ag7 deficiency confined to the B cell compartment. Analysis of these mice, termed NOD BCIID, revealed the presence of functionally competent non-B cell APCs (macrophages/dendritic cells) with normal I-Ag7 expression and capable of activating Ag-reactive T cells. In addition, the secondary lymphoid organs of these mice harbored phenotypically normal CD4+ and CD8+ T cell compartments. Interestingly, whereas control NOD mice harboring I-Ag7-sufficient B cells developed diabetes spontaneously, NOD BCIID mice were resistant to the development of autoimmune diabetes. Despite their diabetes resistance, histologic examination of pancreata from NOD BCIID mice revealed foci of noninvasive peri-insulitis that could be intentionally converted into a destructive process upon treatment with cyclophosphamide. We conclude that I-Ag7-mediated Ag presentation by B cells serves to overcome a checkpoint in T cell tolerance to islet ß cells after their initial targeting has occurred. Overall, this work indicates that the full expression of the autoimmune potential of anti-islet T cells in NOD mice is intimately regulated by B cell-mediated MHC class II Ag presentation.
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H. Noorchashm, D. J. Moore, L. E. Noto, N. Noorchashm, A. J. Reed, A. L. Reed, H. K. Song, R. Mozaffari, A. M. Jevnikar, C. F. Barker, et al. Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice J. Immunol., October 15, 2000; 165(8): 4685 - 4696. [Abstract] [Full Text] [PDF]
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Y.-H. Lou, K.-K. Park, S. Agersborg, P. Alard, and K. S. K. Tung Retargeting T Cell-Mediated Inflammation: A New Perspective on Autoantibody Action J. Immunol., May 15, 2000; 164(10): 5251 - 5257. [Abstract] [Full Text] [PDF]
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A. F. de Vos, A. Fukushima, M. C. Lobanoff, B. P. Vistica, J. C. Lai, J.-C. Grivel, E. F. Wawrousek, S. M. Whitcup, and I. Gery Breakdown of Tolerance to a Neo-Self Antigen in Double Transgenic Mice in Which B Cells Present the Antigen J. Immunol., May 1, 2000; 164(9): 4594 - 4600. [Abstract] [Full Text] [PDF]
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