Pathogenicity of autoreactive T _H 17 cells is modulated by the TRPM7 kinase

The melastatin-like transient receptor potential channel, TRPM7, is crucial for signaling in leukocytes. It harbors a channel domain, permeable to divalent cations as well as a serine/threonine α-kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (T _H 17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic T _H 17 (pT _H 17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pT _H 17 polarization and function as well as in the development of multiple sclerosis (MS), using human T cells and established murine experimental autoimmune encephalomyelitis (EAE) models. Our results reveal an elevated TRPM7 activity in T effector cells derived from the cerebrospinal fluid (CSF) of MS patients, in line with higher functional TRPM7 expression on human T _H 17 cells. Utilizing a mouse line with disrupted kinase activity ( Trpm7 ^R/R ), we uncovered both impaired differentiation of pathogenic T _H 17 cells as well as a significantly milder course of T _H 17-mediated transfer EAE in Trpm7 ^R/R mice compared to Trpm7 ^+/+ controls. In the CNS of Trpm7 ^R/R mice, the number of FOXP3 ⁺ T cells (T _regs ) was increased, while fewer T _H 17 cells infiltrated the CNS due to a migration defect of transferred pT _H 17 cells in the Trpm7 ^R/R hosts and a failure to reactivate in the intestine, due to reduced MHCII signaling. Thus, inactivation of TRPM7 kinase may represent a promising therapeutic strategy targeting both differentiation and reactivation of pT _H 17 cells while preserving T _regs function and thereby dampening CNS inflammation in MS.