CD8+ and CD4+ T cells are critical effector cells of the immune system. CD8+ T cells specifically recognise and kill virally-infected and malignant cells. Mature naïve CD4+ T cells can polarise in the periphery into various lineages that orchestrate immune programmes in response to a variety of challenges such as infection and cancer. The Hedgehog (Hh) signalling pathway has long been known to play a critical role in embryonic development and adult tissue maintenance. Recently, Hh signalling has been shown to be important for CD8+ T cell function downstream of T cell receptor (TCR) signalling. It is unclear how the Hh pathway is mechanistically activated in CD8+ T cells and what role it plays in CD4+ T helper cell (Th) polarisation and function.

This thesis identifies a novel mode of non-canonical Hh signalling through L-type voltage-gated Ca2+ channels that acts downstream of the TCR to induce activation of transcription factor Gli1 to control CD8+ T cell killing. This is in contrast to the canonical Hh signalling pathway, which this thesis shows to be important in regulating CD4+ T helper cell polarisation. Using conditional knockout mouse models and clinically-approved small-molecule inhibitors, this work shows that the canonical Hh pathway acts transcriptionally through Gli3 and metabolically through AMPK to control Th polarisation in vitro and in vivo.

Taken together, this work explores the roles of distinct modes of Hh signalling in the adaptive immune system and may guide future therapeutic approaches to autoimmunity, infection and cancer.