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The Journal of Immunology, 2001, 167: 4351-4357.
Copyright © 2001 by The American Association of Immunologists

Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice1

Siri Atma W. Greeley, Daniel J. Moore, Hooman Noorchashm, Lauren E. Noto, Susan Y. Rostami, Alexander Schlachterman, Howard K. Song, Brigitte Koeberlein, Clyde F. Barker and Ali Naji2

Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Despite the impressive protection of B cell-deficient (µMT-/-) nonobese diabetic (NOD) mice from spontaneous diabetes, existence of mild pancreatic islet inflammation in these mice indicates that initial autoimmune targeting of {beta} cells has occurred. Furthermore, µMT-/- NOD mice are shown to harbor a latent repertoire of diabetogenic T cells, as evidenced by their susceptibility to cyclophosphamide-induced diabetes. The quiescence of this pool of islet-reactive T cells may be a consequence of impaired activation of T lymphocytes in B cell-deficient NOD mice. In this regard, in vitro anti-CD3-mediated stimulation demonstrates impaired activation of lymph node CD4 T cells in µMT-/- NOD mice as compared with that of wild-type counterparts, a deficiency that is correlated with an exaggerated CD4 T cell:APC ratio in lymph nodes of µMT-/- NOD mice. This feature points to an insufficient availability of APC costimulation on a per T cell basis, resulting in impaired CD4 T cell activation in lymph nodes of µMT-/- NOD mice. In accordance with these findings, an islet-reactive CD4 T cell clonotype undergoes suboptimal activation in pancreatic lymph nodes of µMT-/- NOD recipients. Overall, the present study indicates that B cells in the pancreatic lymph node microenvironment are critical in overcoming a checkpoint involving the provision of optimal costimulation to islet-reactive NOD CD4 T cells.




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