| First Author | Varanasi V | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 11 | Pages | 2862-70 |
| PubMed ID | 22773667 | Mgi Jnum | J:190161 |
| Mgi Id | MGI:5448314 | Doi | 10.2337/db11-1784 |
| Citation | Varanasi V, et al. (2012) Cytotoxic mechanisms employed by mouse t cells to destroy pancreatic beta-cells. Diabetes 61(11):2862-70 |
| abstractText | Several cytotoxic mechanisms have been attributed to T cells participating in beta-cell death in type 1 diabetes. However, sensitivity of beta-cells to these mechanisms in vitro and in vivo is likely to be different. Moreover, CD4(+) and CD8(+) T cells may use distinct mechanisms to cause beta-cell demise that possibly involve activation of third-party cytotoxic cells. We used the transfer of genetically modified diabetogenic T cells into normal, mutant, and bone marrow chimeric recipients to test the contribution of major cytotoxic mechanisms in beta-cell death. We found that 1) the killing of beta-cells by CD4(+) T cells required activation of the recipient's own cytotoxic cells via tumor necrosis factor-alpha (TNF-alpha); 2) CD8(+) T-cell cytotoxic mechanisms destroying beta-cells were limited to perforin and Fas ligand, as double knockouts of these molecules abrogated the ability of T cells to cause diabetes; and 3) individual CD8(+) T-cell clones chose their cytotoxic weaponry by a yet unknown mechanism and destroyed their targets via either Fas-independent or Fas-dependent (~40% of clones) pathways. Fas-dependent destruction was assisted by TNF-alpha. |
