Sonic hedgehog signalling in T-cell development and activation

• Published in: Nature Reviews: Immunology 2007-09, Vol.7 (9), p.726-735
• Main Authors: Crompton, Tessa, Outram, Susan V, Hager-Theodorides, Ariadne L
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cells; Cellular signal transduction; Fetus - immunology; Hedgehog Proteins - metabolism; Humans; Immunology; Lymphocyte Activation; Lymphocytes; Physiological aspects; Proteins; review-article; Signal Transduction; T cells; T-Lymphocytes - immunology; Thymus gland; Thymus Gland - immunology
• ISSN: 1474-1733; 1474-1741; 1365-2567
• DOI: 10.1038/nri2151

Key Points Components of the hedgehog signalling pathway are expressed in human and mouse thymi by both stromal and lymphoid cells. Analysis of sonic hedgehog homologue ( Shh ) −/− , glioma-associated oncogene 3 ( Gli3 ) −/− and conditional smoothened ( Smo ) −/− thymi revealed that SHH signalling is necessary for proliferation and survival of double-negative (DN) T cells and for efficient differentiation from DN1 to DN2. The function of hedgehog signalling at the transition from DN to double-positive (DP) cells is controversial, with experimental evidence supporting three possible interpretations: that hedgehog is a negative regulator of differentiation to the DP stage that counteracts the pre-TCR (T-cell receptor) signal; that SHH is a positive regulator of this transition; or, that hedgehog signalling has no influence on thymocyte differentiation after the DN2 stage. The evidence for these three hypotheses is discussed. Analysis of Shh −/− and Gli2ΔN 2 transgenics revealed that SHH signalling influences TCR repertoire selection, CD4–CD8-lineage commitment and differentiation from DP to single-positive (SP) cells, most probably by reducing TCR signal strength. The involvement of SHH signalling in peripheral T-cell function is controversial with different experimental systems supporting three possible interpretations: that hedgehog is a negative regulator of peripheral T-cell activation; that hedgehog is necessary for efficient T-cell activation; or that hedgehog signalling is not involved in T-cell activation. Evidence in favour of these three different models is discussed. Hedgehog signalling proteins, and in particular sonic hedgehog, have a role in T-cell development in the thymus and in peripheral T-cell activation, but, as outlined here, some aspects of their functions remain controversial. The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH-induced signalling is not only important for the differentiation and proliferation of early thymocyte progenitors, but also for modulating T-cell receptor signalling during repertoire selection, with implications for positive selection, CD4 versus CD8 lineage commitment, and clonal deletion of autoreactive cells. We also review the influence of hedgehog