title: Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells.
abstract: The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies.
authors: Institute of Transfusion Medicine, Ulm University, Ulm, Germany.
authors: Stefanie
authors: S
authors: Lindner
authors: Karen
authors: K
authors: Dahlke
authors: Kai
authors: K
authors: Sontheimer
authors: Magdalena
authors: M
authors: Hagn
authors: Christof
authors: C
authors: Kaltenmeier
authors: Thomas F E
authors: TF
authors: Barth
authors: Thamara
authors: T
authors: Beyer
authors: Frank
authors: F
authors: Reister
authors: Dorit
authors: D
authors: Fabricius
authors: Ramin
authors: R
authors: Lotfi
authors: Oleg
authors: O
authors: Lunov
authors: G Ulrich
authors: GU
authors: Nienhaus
authors: Thomas
authors: T
authors: Simmet
authors: Rolf
authors: R
authors: Kreienberg
authors: Peter
authors: P
authors: Möller
authors: Hubert
authors: H
authors: Schrezenmeier
authors: Bernd
authors: B
authors: Jahrsdörfer
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D018956:CD5 Antigens / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D018956:CD5 Antigens; D007378:Interleukins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051193:Toll-Like Receptors; D053804:Granzymes; D000098546:Interleukin-21