Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase
- 1Walther Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany
Abstract
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 -kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (TH17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic TH17 (pTH17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pTH17 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 TH17 cells. Utilizing a mouse line with disrupted kinase activity (Trpm7R/R), we uncovered both impaired differentiation of pathogenic TH17 cells as well as a significantly milder course of TH17-mediated transfer EAE in Trpm7R/R mice compared to Trpm7+/+ controls. In the CNS of Trpm7R/R mice, the number of FOXP3+ T cells (Tregs) was increased, while fewer TH17 cells infiltrated the CNS due to a migration defect of transferred pTH17 cells in the Trpm7R/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 pTH17 cells while preserving Tregs function and thereby dampening CNS inflammation in MS.
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BibTeX
@misc{jacob2026pathogenicity,
title = {{Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase}},
author = {K. Jacob and A. S. Thomann and A. Madlmayr and K. Horner and N. Rodriguez Murillo and D. Lewitz and F. Bauerschmitt and L. A. Gerdes and C. Weber and H. Schulze-Koops and M. Matsushita and T. Gudermann and B. Karner-Hoeger and A. Peters and S. Zierler},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762170},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762170v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase
AU - K. Jacob
AU - A. S. Thomann
AU - A. Madlmayr
AU - K. Horner
AU - N. Rodriguez Murillo
AU - D. Lewitz
AU - F. Bauerschmitt
AU - L. A. Gerdes
AU - C. Weber
AU - H. Schulze-Koops
AU - M. Matsushita
AU - T. Gudermann
AU - B. Karner-Hoeger
AU - A. Peters
AU - S. Zierler
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762170
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762170v1
AB - 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 -kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (TH17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic TH17 (pTH17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pTH17 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 TH17 cells. Utilizing a mouse line with disrupted kinase activity (Trpm7R/R), we uncovered both impaired differentiation of pathogenic TH17 cells as well as a significantly milder course of TH17-mediated transfer EAE in Trpm7R/R mice compared to Trpm7+/+ controls. In the CNS of Trpm7R/R mice, the number of FOXP3+ T cells (Tregs) was increased, while fewer TH17 cells infiltrated the CNS due to a migration defect of transferred pTH17 cells in the Trpm7R/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 pTH17 cells while preserving Tregs function and thereby dampening CNS inflammation in MS.
ER -