title: CD4+ T cell-derived IL-21 and deprivation of CD40 signaling favor the in vivo development of granzyme B-expressing regulatory B cells in HIV patients.
abstract: IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4(+) T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B-expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B-dependent degradation of the TCR-ζ-chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21(+)CD40L(-) Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21-dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
authors.forename: Christof
authors.initials: C
authors.lastname: Kaltenmeier
authors.affiliation: Institute of Molecular Virology, Ulm University, 89081 Ulm, Germany;
authors.forename: Ali
authors.initials: A
authors.lastname: Gawanbacht
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany;
authors.forename: Thamara
authors.initials: T
authors.lastname: Beyer
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany;
authors.forename: Timo
authors.initials: T
authors.lastname: Trzaska
authors.affiliation: Institute of Molecular Virology, Ulm University, 89081 Ulm, Germany;
authors.forename: Johannes Andreas
authors.initials: JA
authors.lastname: van der Merwe
authors.affiliation: Comprehensive Infectious Diseases Center, Ulm University, 89081 Ulm, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Härter
authors.affiliation: Comprehensive Infectious Diseases Center, Ulm University, 89081 Ulm, Germany;
authors.forename: Beate
authors.initials: B
authors.lastname: Grüner
authors.affiliation: Department of Pediatrics, Ulm University, 89075 Ulm, Germany; and.
authors.forename: Dorit
authors.initials: D
authors.lastname: Fabricius
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Red Cross Blood Service Baden-Württemberg - Hessen, 89081 Ulm, Germany.
authors.forename: Ramin
authors.initials: R
authors.lastname: Lotfi
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Red Cross Blood Service Baden-Württemberg - Hessen, 89081 Ulm, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Department of Pediatrics, Ulm University, 89075 Ulm, Germany; and.
authors.forename: Catharina
authors.initials: C
authors.lastname: Schütz
authors.affiliation: Department of Pediatrics, Ulm University, 89075 Ulm, Germany; and.
authors.forename: Manfred
authors.initials: M
authors.lastname: Hönig
authors.affiliation: Department of Pediatrics, Ulm University, 89075 Ulm, Germany; and.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Comprehensive Infectious Diseases Center, Ulm University, 89081 Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Kern
authors.affiliation: Comprehensive Infectious Diseases Center, Ulm University, 89081 Ulm, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Bommer
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Red Cross Blood Service Baden-Württemberg - Hessen, 89081 Ulm, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.affiliation: Institute of Molecular Virology, Ulm University, 89081 Ulm, Germany;
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.affiliation: Institute of Transfusion Medicine, Ulm University, 89081 Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, Red Cross Blood Service Baden-Württemberg - Hessen, 89081 Ulm, Germany bernd.jahrsdoerfer@uni-ulm.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jahrsdörfer
mesh_terms: D016915:AIDS Vaccines / Q000627:therapeutic use; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D053804:Granzymes / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008297:Male; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D014611:Vaccination; D000098546:Interleukin-21
chemical_list: D016915:AIDS Vaccines; D019013:CD40 Antigens; C491731:IKBKG protein, human; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D023201:CD40 Ligand; D051550:I-kappa B Kinase; C509213:GZMB protein, human; D053804:Granzymes; D000098546:Interleukin-21