Interleukin 21–Induced Granzyme B–Expressing B Cells Infiltrate Tumors and Regulate T Cells
| Autor: | Thamara Beyer, Thomas F. E. Barth, Dorit Fabricius, Ramin Lotfi, Kai Sontheimer, Karen Dahlke, Frank Reister, Gerd Ulrich Nienhaus, Peter Möller, Thomas Simmet, Bernd Jahrsdörfer, Rolf Kreienberg, Oleg Lunov, Magdalena Hagn, Stefanie Lindner, Christof Kaltenmeier, Hubert Schrezenmeier |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Regulatory B cells Apoptosis Cell Communication CD5 Antigens Lymphocyte Activation Granzymes Immunophenotyping Immune tolerance Interleukin 21 Lymphocytes Tumor-Infiltrating T-Lymphocyte Subsets Neoplasms Tumor Microenvironment Humans IL-2 receptor Cells Cultured Interleukin 3 B-Lymphocytes Regulatory biology Chemistry Interleukins Toll-Like Receptors Receptors Antigen T-Cell gamma-delta Granzyme B Phenotype Oncology CD1D Immunology Cancer research biology.protein Interleukin 12 Signal Transduction |
| Zdroj: | Cancer Research. 73:2468-2479 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-12-3450 |
| Popis: | 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. Cancer Res; 73(8); 2468–79. ©2013 AACR. |
| Databáze: | OpenAIRE |
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