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Mutually antagonistic signals regulate selection of the t cell repertoire.
| Content Provider | CiteSeerX |
|---|---|
| Author | Stephens, Geoffrey L. Ashwell, Jonathan D. Ignatowicz, Leszek |
| Abstract | The sensitivity of T cells to agonist-induced death during development contrasts with their proliferative responses after agonist challenge in the periphery. The means by which TCR engagement results in these distinct outcomes is incompletely understood. It has been previously hypothesized that glucocorticoids (GC) modulate the threshold for thymocyte activation by blunting the consequences of TCR engagement. In support of this possibility, inhibition of GC production in fetal thymic organ culture was shown to result in CD4 + CD8 + thymocyte apoptosis. This was dependent upon MHC diversity, implying that endogenous GC might regulate antigenspeci®c selection. Similarly, mice expressing reduced GC receptor (GR) levels due to the presence of an antisense transgene have fewer CD4 + CD8 + thymocytes, which was due to an impaired transition from CD4 ± CD8 ± precursors and increased apoptosis. Here we ask how manipulating peptide diversity in the context of reduced GC signaling might affect T cell development and function. In mice with impaired GR expression there was a rescue of thymocyte cellularity and proportions as the diversity of peptides presented by self-MHC was reduced. Furthermore, whereas more CD4 + T cells survived the selection process in mice expressing single-peptide±MHC class II complexes and reduced GR levels, these cells largely failed to recognize the same MHC molecules bound with foreign peptides. Together, these results support a role for endogenous GC in balancing TCR-mediated signals during thymic selection. |
| File Format | |
| Access Restriction | Open |
| Subject Keyword | Cell Repertoire Antagonistic Signal Endogenous Gc Antisense Transgene Fetal Thymic Organ Culture Increased Apoptosis Selection Process Cd4 Cell Gc Production Mhc Diversity Tcr Engagement Result Thymocyte Activation Agonist-induced Death Distinct Outcome Foreign Peptide Tcr Engagement Impaired Gr Expression Thymocyte Cellularity Cd4 Cd8 Thymocytes Development Contrast Antigenspeci Selection Tcr-mediated Signal Cd4 Cd8 Precursor Single-peptide Mhc Class Ii Complex Impaired Transition Mhc Molecule Reduced Gc Signaling Agonist Challenge Gc Receptor Manipulating Peptide Diversity Cell Development Cd4 Cd8 Thymocyte Apoptosis Thymic Selection Proliferative Response Reduced Gr Level |
| Content Type | Text |
