Novel Role for Heparan Sulfate in Thymic Development of CD8+ T Lymphocytes

📖 The Scoop

The thymic stromal microenvironment is crucial for MHC-restricted positive and negative selection of T cells in the thymus to generate functional and self-tolerant alphabeta T cells. Our recent studies have provided new insights into this important process. We found that CD8beta molecules on CD4+CD8+ double positive (DP) thymocytes strongly interact with highly sulfated heparan sulfate (HS) carrying 6-O sulfate groups. Furthermore, we discovered that a HS mimetic (dextran sulfate 500-kDa) can trigger a sustained Ca2+ flux in DP thymocytes that is CD8beta and Slp76, but not Zap70 dependent, and results in a lowering of the TCR activation threshold in DP thymocytes. In contrast, alpha2-3 sialylation of CD8beta molecules on single positive thymocytes and peripheral CD8+ T cells blocks HS binding and prevents the HS-induced Ca2+ flux, an inhibitory effect that is reversed by enzymatic desialylation. Moreover, cortical thymic epithelial cells (cTEC) express high levels of highly sulfated HS and readily form 'rosettes' with thymocytes, rosettes formation being accompanied by a sustained Ca2+ flux in TEC-bound thymocytes, that is substantially blocked by HS mimetics and is markedly reduced in CD8-deficient thymocytes. Additionally, MHC on cTEC synergises with HS to enhance thymocyte rosetting capacity and the extent of the rosette-induced Ca2+ flux in cTEC-bound thymocytes. Collectively, the data imply that the CD8-HS interaction (1) enhances the interaction of DP thymocytes with cTEC expressing self-peptide/MHC complexes and (2) triggers unique CD8-dependent accessory signals, additional to TCR signals, that lower the threshold required for positive selection of TCR clones for self-peptide/MHC complexes.

Genre: No Category (fancy, right?)