Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase

The transient receptor potential channel TRPM7 plays a crucial role in signaling within leukocytes. This channel, which allows divalent cations to pass through and is also kinase in nature, is vital for the development of non-pathogenic T helper 17 (TH17) cells. TRPM7 kinase activity is instrumental in the colonization and activation of T cells within the gut, although when mutated, it contributes to the development of pathogenic TH17 (pTH17) cells that drive autoimmune diseases.

To investigate the role of TRPM7 in pathogenic TH17 cells and multiple sclerosis (MS), researchers utilized human T cells from cerebrospinal fluid (CSF) of MS patients and established murine experimental autoimmune encephalomyelitis (EAE) models. Results indicated elevated TRPM7 activity in T effector cells from MS patients, comparable to higher TRPM7 expression on human TH17 cells.

By introducing a mouse model with disrupted TRPM7 kinase activity (Trpm7R/R), researchers observed impaired differentiation of pathogenic TH17 cells and a significantly milder course of TH17-mediated transfer EAE in these mice compared to Trpm7+/+ controls. In the central nervous system (CNS) of Trpm7R/R mice, there was an increase in FOXP3+ T cells (Tregs) and a reduction in TH17 cells due to impaired migration and reactivation of pTH17 cells in the host and a failure to reactivate in the intestine, attributed to reduced MHCII signaling.

The study suggests that inactivating TRPM7 kinase could be a promising therapeutic strategy, which would target both the differentiation and reactivation of pTH17 cells while preserving the function of Tregs, thereby dampening CNS inflammation in MS.