Novel role for heparan sulfate in thymic development of CD8⁺ T lymphocytes
Date
2015
Authors
Simon Davis, David Anak
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Abstract
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.
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heparan sulfate, thymopoiesis, lymphopoiesis, T-cells
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Thesis (PhD)
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