CD4+ T cells are part of the adaptive immune system and can polarise into different T helper (Th) cell subsets to orchestrate large-scale immune responses. T helper fate choice is determined after naïve CD4+ T cells encounter cognate antigen and co-stimulation by the surrounding cytokine milieu and is guided by subset-specific master transcription factors. Each T helper subset produces a specific set of effector cytokines to modulate key immune responses in the context of Type I, II, and III immunity. Th1 cells produce IFNγ, IL-2, and TNFα and together with ILC1 and γδ1 T cells drive the Type I immune response which is important for antiviral, antibacterial and anti-tumour immunity. Th2 cells, along with ILC2s secrete IL-4, IL-5, and IL-13 which act as the Type II immune response to protect against extracellular pathogens such as parasitic helminths. Th17 cells along with ILC3s and yd17s produce IL-17 and IL-22 as part of the Type III in response to bacterial and fungal infections at mucosal surfaces while Tregs act to suppress immune responses and maintain homeostasis (Krishnarajah and Becher, 2022). And Tfh cells are important for the formation of germinal centres (Jiang and Dong, 2013). In recent years novel Th subsets such as Th9 and Th22 have been identified (Schmitt et al., 2014, Jiang et al., 2021). Tfh, Th9 and Th22 cells have not yet been explored with regards to Hedgehog signalling and are not part of this review.

Th subsets not only play a critical role in physiological immune responses but are also key drivers of numerous malignant, allergic and autoimmune disease processes (Yasuda et al., 2019, Harker and Lloyd, 2023, Basu et al., 2021). Therefore, there has been great interest in identifying therapeutic entry points to modulate Th polarisation in a disease context. While polarising cytokines and master transcription factors are comparatively well known, the signalling pathways guiding Th polarisation, some of which potentially amenable to pharmacological targeting, are incompletely understood.

Hedgehog signalling is an evolutionary highly conserved classical cell-cell communication pathway critical for embryonic development and adult tissue maintenance. Like other morphogen signalling pathways, Hedgehog ligands (Sonic, Indian or Desert Hedgehog) are produced and secreted by ligand-producing cells. The ligands are subsequently detected by receiving cells that transduce the signal to the nucleus and mount a Hedgehog-specific target gene programme (Briscoe and Therond, 2013).

Strikingly, vertebrate Hedgehog signalling is tied to the primary cilium (Huangfu et al., 2003, Corbit et al., 2005, Rohatgi et al., 2007) – a hairlike organelle protruding from the cell body: Hedgehog ligands are received by the transmembrane receptor Patched (Ptch) at the base of the primary cilium. Upon ligand binding, Ptch releases its inhibition of the key signal transducer Smoothened (Smo) and Smo moves into the primary cilium and activates one of three Gli transcription factors (Gli1, 2, and 3), that subsequently move into the nucleus to initiate a Hedgehog-mediated target gene response (Zhang and Beachy, 2023). Interestingly, the Gli2 and Gli3 can be processed into Gli activator (GliA) and Gli repressor (GliR) transcription factors with opposing roles on transcription.

Interestingly, the immune synapse formed by T cells with antigen presenting cells is morphologically and functionally very similar to the primary cilium and it has been demonstrated that Hedgehog signalling at the immunological synapse is critical for CD8+ T cell function (de la Roche et al., 2016, de la Roche et al., 2013).

The similarities between the primary cilium and T cell immune synapses, as well as the well-accepted role of Hedgehog in controlling cell fate decisions in many tissues, make Hedgehog an attractive pathway to investigate in CD4+ T helper cell polarisation and cell-fate choice.