Abstract
TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells, allowing us to determine the role of CD40-CD154 signals in regulation of autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T(R) cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T(R) cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to suppression.
| Original language | English |
|---|---|
| Pages (from-to) | 9345-50 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 101 |
| Issue number | 25 |
| DOIs | |
| Publication status | Published - 2004 |
Keywords
- Animals
- Antigens, CD40
- CD40 Ligand
- CD8-Positive T-Lymphocytes
- Diabetes Mellitus, Type 1
- Disease Models, Animal
- Flow Cytometry
- Islets of Langerhans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- RNA, Messenger