title: Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers.
abstract: The monoclonal anti-CD20 antibody rituximab (RTX) depletes B cells in the treatment of lymphoma and autoimmune disease, and contributes to alloantibody reduction in transplantation across immunologic barriers. The effects of RTX on T cells are less well described. T-follicular helper (Tfh) cells provide growth and differentiation signals to germinal center (GC) B cells to support antibody production, and suppressive T-follicular regulatory (Tfr) cells regulate this response. In mice, both Tfh and Tfr are absolutely dependent on B cells for their formation and on the GC for their maintenance. In this study, we demonstrate that RTX treatment results in a lack of GC B cells in human lymph nodes without affecting the Tfh or Tfr cell populations. These data demonstrate that human Tfh and Tfr do not require an ongoing GC response for their maintenance. The persistence of Tfh and Tfr following RTX treatment may permit rapid reconstitution of the pathological GC response once the B-cell pool begins to recover. Strategies for maintaining remission after RTX therapy will need to take this persistence of Tfh into account.
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Wallin
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Jolly
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: Ondřej
authors.initials: O
authors.lastname: Suchánek
authors.affiliation: Department of Surgery, University of Cambridge School of Clinical Medicine and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom; and.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: Marion
authors.initials: M
authors.lastname: Espéli
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: David R W
authors.initials: DR
authors.lastname: Jayne
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, United Kingdom.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Linterman
authors.affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom;
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018959:CD57 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D054380:Receptors, CXCR5 / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D018959:CD57 Antigens; C095085:CXCR5 protein, human; D007155:Immunologic Factors; D054380:Receptors, CXCR5; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000069283:Rituximab