Abstract
In the thymus, developing T cells receive signals that determine lineage choice, specificity, MHC restriction and tolerance to self-antigen. One way in which thymocytes receive instruction is by secretion of Sonic hedgehog (Shh) from thymic epithelial cells. We have previously shown that Hedgehog (Hh) signalling in the thymus decreases the CD4:CD8 single-positive (SP) thymocyte ratio. Here, we present data indicating that double-positive (DP) thymocytes are Hh-responsive and that thymocyte-intrinsic Hh signalling plays a role in modulating the production of CD4+ (SP4), CD8+ (SP8) and unconventional T-cell subsets. Repression of physiological Hh signalling in thymocytes altered the proportions of DP and SP4 cells. Thymocyte-intrinsic Hh-dependent transcription also attenuated both the production of mature SP4 and SP8 cells, and the establishment of peripheral T-cell compartments in TCR-transgenic mice. Additionally, stimulation or withdrawal of Hh signals in the WT foetal thymus impaired or enhanced upregulation of the CD4 lineage-specific transcription factor Gata3 respectively. These data together suggest that Hh signalling may play a role in influencing the later stages of thymocyte development.
Highlights
During ab T-cell development, thymocytes migrate through distinct thymic microenvironments, receiving signals that determine their lineage choice, MHC restriction, antigen specificity and ability to discriminate between self and non-self
Repression of Hh signalling in thymocytes moderately increases the proportion of SP4 cells
We have previously shown that activation of Hh signalling in thymocytes causes a decrease in the production of SP4 cells [16]
Summary
During ab T-cell development, thymocytes migrate through distinct thymic microenvironments, receiving signals that determine their lineage choice, MHC restriction, antigen specificity and ability to discriminate between self and non-self. The events controlling T-cell lineage choice and selection in the thymus are not fully understood. Several models attempt to explain how different TCR signals influence thresholds for thymocyte selection and differentiation during development [2]. Recent models hypothesise that TCR signals of differing strength, duration and kinetics are integrated with local stromal influences [3], including cytokine signalling [4, 5], morphogen signalling [6] and Notch signalling [7], to regulate lineage choice and selection.
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