Cross-linking of T-cell receptors on double-positive thymocytes induces a cytokine-mediated stromal activation process linked to cell death.

AUTOR(ES)
RESUMO

To investigate molecular events associated with the intrathymic process of negative selection, we established an in vivo system using an anti-CD3 epsilon monoclonal antibody to induce synchronous apoptosis in the thymus of AND T-cell receptor (TCR) transgenic RAG-2-/- mice in a non-selecting haplotype. This model eliminates endogenous negative selection as well as gene activation in the mature thymocyte compartment, offering an ideal source of tester (anti-CD3 epsilon-treated) and driver (untreated) thymus RNA for representational difference analysis (RDA). Fourteen mRNA sequences that are up-regulated in the thymuses of such mice 2-6 h after anti-CD3 epsilon treatment were identified. Surprisingly, the majority of these transcripts were derived from stromal cells rather than the TCR-cross-linked CD4+CD8+TCRlow thymocytes including the macrophage products IL-1, the chemokine Mig and the transcription factor LRG-21. IFN-gamma secretion from the CD4+CD8+TCRlow thymocytes regulates macrophage Mig production. Three other cytokines (IL-4, GM-CSF and TNF-alpha), known to activate a variety of stromal cells, are also induced in the same thymocyte population undergoing apoptosis. Expression of a TNF-alpha-inducible gene, B94, in stromal cells after TCR ligation further supports the notion of cross-talk between thymocytes and stroma. Thus, TCR-triggered immature thymocytes elaborate cytokines which may regulate the delivery of further signals from stromal cells required for apoptosis.

ACESSO AO ARTIGO

Documentos Relacionados