CD154-dependent priming of diabetogenic CD4(+) T cells dissociated from activation of antigen-presenting cells.
We followed the fate of K(d)- or I-A(g7)-restricted beta cell-autoreactive T cells in monoclonal TCR-transgenic NOD mice expressing or lacking CD154. 8.3-NOD.RAG-2(-/-)/CD154(-/-) mice, which bear autoreactive CD8(+) T cells, developed diabetes with the same incidence and tempo as 8.3-NOD.RAG-2(-/-)/CD154(+) mice. Recruitment of CD154(-/-) 8.3-CD8(+) CTL was accelerated by CD154(+)CD4(+) T cells, by expression of a B7.1 transgene in beta cells or by treatment of the mice with CpG-DNA or an agonistic anti-CD40 antibody. In contrast, the autoreactive CD4(+) T cells maturing in 4.1-NOD.RAG-2(-/-) mice lost their diabetogenic potential if they lacked CD154, even in the presence of CD154(+)CD4(+) T cells, B7.1 molecules on beta cells, CpG-DNA treatment, or systemic CD40 ligation. These results demonstrate the existence of a novel, CD154-dependent pathway of CD4(+) T cell activation that is independent of CD40-mediated activation of APCs.
Amrani
Abdelaziz
A
Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Center, The University of Calgary, Faculty of Medicine, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1.
Serra
Pau
P
Yamanouchi
Jun
J
Han
Bingye
B
Thiessen
Shari
S
Verdaguer
Joan
J
Santamaria
Pere
P
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D019672:Genes, T-Cell Receptor; D007515:Islets of Langerhans / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010179:Pancreas / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D018122:B7-1 Antigen; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D023201:CD40 Ligand