RT Journal Article
SR Electronic
T1 Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200033
DO 10.1212/NXI.0000000000200033
VO 9
IS 6
A1 Jérémy Morille
A1 Marion Mandon
A1 Stéphane Rodriguez
A1 David Roulois
A1 Simon Leonard
A1 Alexandra Garcia
A1 Sandrine Wiertlewski
A1 Emmanuelle Le Page
A1 Laureline Berthelot
A1 Arnaud Nicot
A1 Camille Mathé
A1 Flora Lejeune
A1 Karin Tarte
A1 Céline Delaloy
A1 Patricia Amé
A1 David Laplaud
A1 Laure Michel
YR 2022
UL http://nn.neurology.org/content/9/6/e200033.abstract
AB Background and Objectives Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS).Methods The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event.Results The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis.Discussion Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.cDNA=complementary DNA; CIS=clinically isolated syndrome; EAE=experimental autoimmune encephalomyelitis; FDC=follicular dendritic cell; GEO=Gene Expression Omnibus; HC=healthy control; IQR=interquartile range; MS=multiple sclerosis; NIND=noninflammatory neurologic disease; PBMC=peripheral blood mononuclear cell; RRMS=relapsing-remitting multiple sclerosis; Tfh=follicular helper T; Tfr=follicular regulatory T; TLS=tertiary lymphoid structures