title: Impaired activation of islet-reactive CD4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice.
abstract: Despite the impressive protection of B cell-deficient (muMT(-/-)) 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, muMT(-/-) 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 muMT(-/-) 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 muMT(-/-) 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 muMT(-/-) NOD mice. In accordance with these findings, an islet-reactive CD4 T cell clonotype undergoes suboptimal activation in pancreatic lymph nodes of muMT(-/-) 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.
authors.affiliation: Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Greeley
authors.forename: D J
authors.initials: DJ
authors.lastname: Moore
authors.forename: H
authors.initials: H
authors.lastname: Noorchashm
authors.forename: L E
authors.initials: LE
authors.lastname: Noto
authors.forename: S Y
authors.initials: SY
authors.lastname: Rostami
authors.forename: A
authors.initials: A
authors.lastname: Schlachterman
authors.forename: H K
authors.initials: HK
authors.lastname: Song
authors.forename: B
authors.initials: B
authors.lastname: Koeberlein
authors.forename: C F
authors.initials: CF
authors.lastname: Barker
authors.forename: A
authors.initials: A
authors.lastname: Naji
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003520:Cyclophosphamide / Q000009:adverse effects; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000209:etiology / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D003520:Cyclophosphamide