Impaired activation of islet-reactive CD4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice

Despite the impressive protection of B cell-deficient (mu MT-/-) nonobese d iabetic (NOD) mice from spontaneous diabetes, existence of mild pancreatic islet inflammation in these mice indicates that initial autoimmune targetin g of beta cells has occurred. Furthermore, mu MT-/- NOD mice are shown to h arbor a latent repertoire of diabetogenic T cells, as evidenced by their su sceptibility to cyclophosphamide-induced diabetes. The quiescence of this p ool of islet-reactive T cells may be a consequence of impaired activation o f T lymphocytes in B cell-deficient NOD mice. In this regard, in vitro anti -CD3-mediated stimulation demonstrates impaired activation of lymph node CD 4 T cells in mu MT-/- NOD mice as compared with that of wild-type counterpa rts, a deficiency that is correlated with an exaggerated CD4 T cell:APC rat io in lymph nodes of mu MT-/- NOD mice. This feature points to an Insuffici ent availability of APC costimulation on a per T cell basis, resulting in i mpaired CD4 T cell activation in lymph nodes of mu MT-/- NOD mice. In accor dance with these findings, an islet-reactive CD4 T cell clonotype undergoes suboptimal activation in pancreatic lymph nodes of mu MT-/- NOD recipients . Overall, the present study indicates that B cells in the pancreatic lymph node microenvironment are critical in overcoming a checkpoint involving th e provision of optimal costimulation to islet-reactive NOD CD4 T cells.