Investigating the role of TCR signalling during T cell development
Publisher
Metadata
Show full item recordAbstract
The thymus generates multiple T cell populations from an early common CD4(-)
CD8(-) double negative (DN) progenitor. Conventional αβ T cells, such as CD4(+)
and CD8(+) T cells undergo thymic positive selection on partial agonist
interactions with self-peptide/MHC, whereas unconventional TCRαβ(+)CD8αα(+)
intraepithelial lymphocytes (IELs) and regulatory T cells (Tregs), are thought to
require full agonist interactions. By contrast, very little is known about how γδ T
cells undergo selection. While it has been suggested that IL-17A-secreting γδ T
cells rely on strong TCR signals resulting from potential interactions with a
ligand, several studies have led to opposite conclusions. This thesis
investigates the role of TCR signal strength during the early stages of
thymocyte development, and how this dictates subsequent T cell fate.
We show that FVB/n mice have relatively few unconventional
TCRαβ(+)CD8αα(+) IELs in comparison to C57Bl/6 animals. This depleted IEL
compartment correlated with reduced thymic IEL progenitors, an inefficient
preTCR-driven DN-to-DP transition, and a relatively increased expression of full
length pTαa transcripts in CD44(-)CD25(+) DN3 cells. Transgenic over-expression
of pTαa in the absence of pTαb transcripts mimicked the phenotype of FVB/n
animals. CD5 levels on DN3 cells from pTαa transgenic mice indicate that
preTCR signalling was weaker than in C57Bl/6 mice, suggesting that signal
strength at the β-selection checkpoint may influence subsequent selection of
mature T cell populations. Consistent with this, we show that OT-II mice, which
express a transgenic TCRαβ from an early DN stage of thymocyte
6
development, and which have high levels of CD5 on DN3 cells, have a relatively
increased unconventional TCRαβ(+)CD8αα(+)IEL compartment. For γδ T cell
development, we also show that weakening signal strength impairs the
development of IL-17A-secreting γδ T cells. However, increasing signal
strength, through the use of a cross-linking antibody, does not favour their
development as predicted. These seemingly paradoxical observations are
explored further.
Taken together, these data suggest that the quality or quantity of TCR-mediated
signals early in T cell development have fundamental consequences for
subsequent T cell selection events that differentially generate distinct T cell
subsets.
Authors
Grandjean, Capucine L-ACollections
- Theses [3348]