Abstract
Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt+ cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt+ cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow.
Highlights
A recent study by Littman and colleagues[19] revealed that, along with Il17a, Il17f, Il23r, Ccl[20], Il1r1 or Ltb4r1, Tmem176a and b are part of the highly restricted group of 11 genes whose expression is directly dependent on RORγ t in Th17 cells
The discovery of Th17 cells as a distinct differentiation of T cell has sparked an intense research on their role in host defence and immune-mediated inflammatory diseases (IMIDs)
Much attention has been given to these cells through the prism of key cytokines they produce, namely IL-17A, IL-17F, IL-22 or GM-CSF (CSF2), leading to mucosal defence and repair
Summary
A recent study by Littman and colleagues[19] revealed that, along with Il17a, Il17f, Il23r, Ccl[20], Il1r1 or Ltb4r1, Tmem176a and b are part of the highly restricted group of 11 genes whose expression is directly dependent on RORγ t in Th17 cells. As part of the Immunological Genome Project, Colonna and colleagues highlighted several ILC-specific genes including Tmem176a and b, whose expression was remarkably higher in ILC3 subsets than in group 1 and 2 ILCs25. These findings logically raise the question whether Tmem176a and b play a role in type 17 immunity-related RORγ t+ lymphocytes, including Th17 cells and ILC3s, which is yet to be unveiled. We have characterised Tmem176a and b expression in RORγ t+ lymphocytes at transcriptional and protein levels and present evidence that both genes exert a redundant ion channel function related to a colocalisation in close proximity to the Golgi apparatus
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