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 (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.
Greeley
S A
SA
Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Moore
D J
DJ
Noorchashm
H
H
Noto
L E
LE
Rostami
S Y
SY
Schlachterman
A
A
Song
H K
HK
Koeberlein
B
B
Barker
C F
CF
Naji
A
A
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
D003520:Cyclophosphamide