title: Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis.
abstract: Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Tessa
authors.initials: T
authors.lastname: Dhaeze
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Evelyn
authors.initials: E
authors.lastname: Peelen
authors.affiliation: Viral Diseases Unit, Operational Direction of Transmitted and Infectious Diseases, Scientific Institute of Public Health, 1200 Brussels, Belgium;
authors.forename: Anneleen
authors.initials: A
authors.lastname: Hombrouck
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Liesbet
authors.initials: L
authors.lastname: Peeters
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium; Rehabilitation and Multiple Sclerosis Center, 3900 Overpelt, Belgium;
authors.forename: Bart
authors.initials: B
authors.lastname: Van Wijmeersch
authors.affiliation: Hospital East-Limburg, 3600 Genk, Belgium; and.
authors.forename: Nele
authors.initials: N
authors.lastname: Lemkens
authors.affiliation: Hospital East-Limburg, 3600 Genk, Belgium; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Lemkens
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Veerle
authors.initials: V
authors.lastname: Somers
authors.affiliation: de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Bieke
authors.initials: B
authors.lastname: Broux
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium;
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium; School of Life Sciences, Transnational University Limburg, 3590 Diepenbeek, Belgium; niels.hellings@uhasselt.be.
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood; D053301:B-Cell Maturation Antigen / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000276:immunology*; D008297:Male; D008745:Methylation; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014611:Vaccination; D055815:Young Adult
chemical_list: D000906:Antibodies; D053301:B-Cell Maturation Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007252:Influenza Vaccines; C086966:TNFRSF17 protein, human