Cytotoxic mechanisms employed by mouse T cells to destroy pancreatic β-cells.
Diabetes, 2012/11;61(11):2862-70.
Varanasi V[1], Avanesyan L, Schumann DM, Chervonsky AV
Affiliations
PMID: 22773667DOI: 10.2337/db11-1784
Impact factor: 9.337
Abstract
Several cytotoxic mechanisms have been attributed to T cells participating in β-cell death in type 1 diabetes. However, sensitivity of β-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 β-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 β-cell death. We found that 1) the killing of β-cells by CD4⁺ T cells required activation of the recipient's own cytotoxic cells via tumor necrosis factor-α (TNF-α); 2) CD8⁺ T-cell cytotoxic mechanisms destroying β-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-α.
MeSH terms
Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Clone Cells; Cytotoxicity, Immunologic; Diabetes Mellitus, Type 1; Fas Ligand Protein; Gene Expression Regulation; Insulin-Secreting Cells; Lymphocyte Activation; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Pore Forming Cytotoxic Proteins; RNA, Messenger; Signal Transduction; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha
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