The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation.
TNF-alpha has been linked to the development of type 1 diabetes (T1D). We previously reported that neonatal treatment of nonobese diabetic (NOD) mice with TNF-alpha accelerated the onset of T1D, whereas TNF-alpha blockade in the same time period resulted in a complete absence of diabetes. The mechanisms by which TNF-alpha modulates development of T1D in NOD mice remain unclear. Here we tested the effects of TNF-alpha on the maturation of dendritic cells (DCs) in the NOD mouse. We found that neonatal treatment with TNF-alpha caused an increase in expression of maturation markers on CD11c(+)CD11b(+) DC subpopulations, whereas treatment with anti-TNF-alpha resulted in a decrease in expression of maturation markers in the CD11c(+)CD11b(+) subset. Moreover, neonatal treatment with TNF-alpha resulted in skewed development of a CD8alpha(+)CD11b(-)CD11c(+) DC subset such that TNF-alpha decreases the CD8alpha(+)CD11c(+) DC subset, increases the CD11c(+)CD11b(+) subset, and causes an increase in the expression of CD40 and CD54 on mature DCs capable of inducing immunity. Anti-TNF-alpha-treated mice had an increase in the CD8alpha(+)CD11c(+) DCs. Notably, adoptively transferred naïve CD4(+) T cells from BDC2.5 T cell receptor transgenic mice proliferated in the pancreatic lymph nodes in TNF-alpha-treated NOD mice but not in anti-TNF-alpha-treated mice. Finally, we show that anti-TNF-alpha-treated mice showed immunological tolerance to islet cell proteins. We conclude that TNF-alpha plays an important role in the initiation of T1D in the NOD mouse by regulating the maturation of DCs and, thus, the activation of islet-specific pancreatic lymph node T cells.
Lee
Li-Fen
LF
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Xu
Baohui
B
Michie
Sara A
SA
Beilhack
Georg F
GF
Warganich
Tibor
T
Turley
Shannon
S
McDevitt
Hugh O
HO
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
D000906:Antibodies; D015703:Antigens, CD; D014409:Tumor Necrosis Factor-alpha