Role of Hedgehog signalling at the transition from double‐positive to single‐positive thymocyte

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.

The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice

“…As our findings were in contrast to several other reports describing an influence of Hh signaling on the transition from the double-positive (DP) to the single-positive (SP) stage of thymocyte development [22], [23], [24], we decided to repeat the analyses with mice backcrossed to the C57BL/6 background. Although the overall thymic cellularity (Figure 1A) and the percentages of double-negative (DN) thymocytes (Figure 1B,C) were similar in both genotypes, we found that the relative number of DP thymocytes was increased in Ptch flox/flox CD4Cre +/− mutant mice while the percentages of CD4 and CD8 SP thymocytes were decreased (Figure 1C).…”

The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus

“…Neutralisation of Hh signals in FTOC by treatment with neutralising anti-Hh monoclonal antibody has previously been shown to promote T-cell development, and increase differentiation from CD3 hi DP to mature SP cell and to increase the CD4SP:CD8SP ratio [19, 20]. Hhip-treatment significantly increased the proportion of CD3 hi thymocytes in the WT FTOC, compared to control untreated cultures (Figure 4C-4D).…”

An Overview of the Intrathymic Intricacies of T Cell Development

“…Data for the differentiation, proliferation, and survival of the earliest DN thymocyte subsets, the transition from DN to DP, as a negative regulator of pre-TCR-induced thymocyte expansion (79)(80)(81)(82)(83), the transition from DP to SP, for TCR repertoire selection, at the CD4/ CD8 lineage decision (84,85), and negative selection (83) all support a role for Hh signaling in T cell development. In contrast, other work showed that the Hh signal transducer Gli1 is not needed to mediate the effects of Hh signaling at early stages of thymocyte differentiation (86), and gain-and loss-of-function genetic models of Smoothened show that it is not required for adult BM HSC self-renewal or differentiation or for thymocyte development (87).…”