Biology subjects

Thomann, A. S.

Publications and source records attributed to Thomann, A. S..

2 recordsLinked to original sources

bioRxiv2026

Pathogenicity of autoreactive TH17 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 -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.

immunology↗

bioRxiv2023

T:B cell communication in ectopic lymphoid follicles in CNS autoimmunity

Meningeal ectopic lymphoid follicle-like structures (eLFs) have been described in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), but their role in CNS autoimmunity is unclear. To analyze the cellular phenotypes and interactions within these structures, we employed a Th17 adoptive transfer EAE model featuring formation of large, numerous eLFs. Single-cell transcriptomic analysis revealed that clusters of activated B cells and B1/Marginal Zone-like B cells are overrepresented in the CNS and identified B cells poised for undergoing antigen-driven germinal center (GC) reactions and clonal expansion in the CNS. Furthermore, CNS B cells showed enhanced capacity for antigen presentation and immunological synapse formation compared to peripheral B cells. To directly visualize Th17:B cell cooperation in eLFs, we labeled Th17 cells with a ratiometric calcium sensor, and tracked their interactions with tdTomato-labeled B cells in real-time. Thereby, we demonstrated for the first time that T and B cells form long-lasting antigen-specific contacts in meningeal eLFs that result in reactivation of autoreactive T cells. Consistent with these findings, autoreactive T cells depended on CNS B cells to maintain a pro-inflammatory cytokine profile in the CNS. Collectively, our study reveals that extensive T:B cell cooperation occurs in meningeal eLFs in our model promoting differentiation and clonal expansion of B cells, as well as reactivation of CNS T cells and thereby supporting smoldering inflammatory processes within the CNS compartment. Our results provide valuable insights into the function of eLFs and may provide a direction for future research in MS.

immunology↗