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IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling
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Zeitschriftentitel: | Blood |
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Personen und Körperschaften: | , , , , , , , |
In: | Blood, 124, 2014, 21, S. 1413-1413 |
Format: | E-Article |
Sprache: | Englisch |
veröffentlicht: |
American Society of Hematology
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Schlagwörter: |
author_facet |
Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert |
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author |
Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert |
spellingShingle |
Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert Blood IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling Cell Biology Hematology Immunology Biochemistry |
author_sort |
jahrsdörfer, bernd |
spelling |
Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v124.21.1413.1413 <jats:title>Abstract</jats:title> <jats:p>Recently, we and others found that B cells differentiate into regulatory B cells (Breg) in response to interleukin (IL-)21. Of note, the key characteristic of human IL-21-induced Breg is expression of the serine protease granzyme B (GrB), whereas murine Breg, which require both IL-21 and CD40 ligand (CD40L) for their induction, predominantly express the immunosuppressive cytokine IL-10. Using two different disease models and various immunological methods, we further characterized the conditions leading to Breg differentiation in humans. Here, we demonstrate that in humans CD40L determines whether IL-21 induces differentiation of B cells into plasma cells (CD40L presence) or into GrB+ Breg (CD40L absence), which can directly control T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Furthermore, we show that GrB+ Breg are circulating at high frequencies in the peripheral blood of untreated, highly viremic HIV patients, but not in healthy subjects. Of note, HIV-infected CD4+ T cells express IL-21, but not CD40L, and induce a GrB+ regulatory phenotype in healthy third party B cells in vitro. Consequently, addition of CD40L multimers can compensate for this insufficient T helper cell function, resulting in increased plasma cell/Breg ratios. Moreover, we investigated a patient with a congenital defect of Nuclear-Factor-kappa-B-Essential-Modulator (NEMO), which is essential for normal CD40 signaling. Even in the presence of viral infections, when CD4+ T helper cells from such patients are highly activated with strong expression of IL-21, they are not able to establish sufficient antibody responses. Instead, we found this patient to almost exclusively harbor B cells with a regulatory phenotype including high basal levels of GrB. When untreated NEMO B cells were co-cultured with allogeneic T cells from a healthy third party donor, these T cells failed to proliferate and to survive in response to a 6-day stimulation with anti-CD3/CD28 antibodies, an effect not observed with B cells from healthy donors. Since NEMO B cells lack normal CD40 signaling, our findings unequivocally demonstrate that in contrast to murine Breg IL-21-dependent induction of human Breg can occur in a CD40-independent fashion.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling Blood |
doi_str_mv |
10.1182/blood.v124.21.1413.1413 |
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Biologie Medizin Chemie und Pharmazie |
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American Society of Hematology, 2014 |
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American Society of Hematology, 2014 |
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title |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_unstemmed |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_full |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_fullStr |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_full_unstemmed |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_short |
IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_sort |
il-21-mediated generation of human regulatory b cells occurs independently of cd40 signaling |
topic |
Cell Biology Hematology Immunology Biochemistry |
url |
http://dx.doi.org/10.1182/blood.v124.21.1413.1413 |
publishDate |
2014 |
physical |
1413-1413 |
description |
<jats:title>Abstract</jats:title>
<jats:p>Recently, we and others found that B cells differentiate into regulatory B cells (Breg) in response to interleukin (IL-)21. Of note, the key characteristic of human IL-21-induced Breg is expression of the serine protease granzyme B (GrB), whereas murine Breg, which require both IL-21 and CD40 ligand (CD40L) for their induction, predominantly express the immunosuppressive cytokine IL-10. Using two different disease models and various immunological methods, we further characterized the conditions leading to Breg differentiation in humans. Here, we demonstrate that in humans CD40L determines whether IL-21 induces differentiation of B cells into plasma cells (CD40L presence) or into GrB+ Breg (CD40L absence), which can directly control T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Furthermore, we show that GrB+ Breg are circulating at high frequencies in the peripheral blood of untreated, highly viremic HIV patients, but not in healthy subjects. Of note, HIV-infected CD4+ T cells express IL-21, but not CD40L, and induce a GrB+ regulatory phenotype in healthy third party B cells in vitro. Consequently, addition of CD40L multimers can compensate for this insufficient T helper cell function, resulting in increased plasma cell/Breg ratios. Moreover, we investigated a patient with a congenital defect of Nuclear-Factor-kappa-B-Essential-Modulator (NEMO), which is essential for normal CD40 signaling. Even in the presence of viral infections, when CD4+ T helper cells from such patients are highly activated with strong expression of IL-21, they are not able to establish sufficient antibody responses. Instead, we found this patient to almost exclusively harbor B cells with a regulatory phenotype including high basal levels of GrB. When untreated NEMO B cells were co-cultured with allogeneic T cells from a healthy third party donor, these T cells failed to proliferate and to survive in response to a 6-day stimulation with anti-CD3/CD28 antibodies, an effect not observed with B cells from healthy donors. Since NEMO B cells lack normal CD40 signaling, our findings unequivocally demonstrate that in contrast to murine Breg IL-21-dependent induction of human Breg can occur in a CD40-independent fashion.</jats:p>
<jats:sec>
<jats:title>Disclosures</jats:title>
<jats:p>No relevant conflicts of interest to declare.</jats:p>
</jats:sec> |
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author | Jahrsdörfer, Bernd, Kaltenmeier, Christof, Gawanbacht, Ali, Beyer, Thamara, Schütz, Catharina, Hönig, Manfred, Kirchhoff, Frank, Schrezenmeier, Hubert |
author_facet | Jahrsdörfer, Bernd, Kaltenmeier, Christof, Gawanbacht, Ali, Beyer, Thamara, Schütz, Catharina, Hönig, Manfred, Kirchhoff, Frank, Schrezenmeier, Hubert, Jahrsdörfer, Bernd, Kaltenmeier, Christof, Gawanbacht, Ali, Beyer, Thamara, Schütz, Catharina, Hönig, Manfred, Kirchhoff, Frank, Schrezenmeier, Hubert |
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description | <jats:title>Abstract</jats:title> <jats:p>Recently, we and others found that B cells differentiate into regulatory B cells (Breg) in response to interleukin (IL-)21. Of note, the key characteristic of human IL-21-induced Breg is expression of the serine protease granzyme B (GrB), whereas murine Breg, which require both IL-21 and CD40 ligand (CD40L) for their induction, predominantly express the immunosuppressive cytokine IL-10. Using two different disease models and various immunological methods, we further characterized the conditions leading to Breg differentiation in humans. Here, we demonstrate that in humans CD40L determines whether IL-21 induces differentiation of B cells into plasma cells (CD40L presence) or into GrB+ Breg (CD40L absence), which can directly control T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Furthermore, we show that GrB+ Breg are circulating at high frequencies in the peripheral blood of untreated, highly viremic HIV patients, but not in healthy subjects. Of note, HIV-infected CD4+ T cells express IL-21, but not CD40L, and induce a GrB+ regulatory phenotype in healthy third party B cells in vitro. Consequently, addition of CD40L multimers can compensate for this insufficient T helper cell function, resulting in increased plasma cell/Breg ratios. Moreover, we investigated a patient with a congenital defect of Nuclear-Factor-kappa-B-Essential-Modulator (NEMO), which is essential for normal CD40 signaling. Even in the presence of viral infections, when CD4+ T helper cells from such patients are highly activated with strong expression of IL-21, they are not able to establish sufficient antibody responses. Instead, we found this patient to almost exclusively harbor B cells with a regulatory phenotype including high basal levels of GrB. When untreated NEMO B cells were co-cultured with allogeneic T cells from a healthy third party donor, these T cells failed to proliferate and to survive in response to a 6-day stimulation with anti-CD3/CD28 antibodies, an effect not observed with B cells from healthy donors. Since NEMO B cells lack normal CD40 signaling, our findings unequivocally demonstrate that in contrast to murine Breg IL-21-dependent induction of human Breg can occur in a CD40-independent fashion.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> |
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spelling | Jahrsdörfer, Bernd Kaltenmeier, Christof Gawanbacht, Ali Beyer, Thamara Schütz, Catharina Hönig, Manfred Kirchhoff, Frank Schrezenmeier, Hubert 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood.v124.21.1413.1413 <jats:title>Abstract</jats:title> <jats:p>Recently, we and others found that B cells differentiate into regulatory B cells (Breg) in response to interleukin (IL-)21. Of note, the key characteristic of human IL-21-induced Breg is expression of the serine protease granzyme B (GrB), whereas murine Breg, which require both IL-21 and CD40 ligand (CD40L) for their induction, predominantly express the immunosuppressive cytokine IL-10. Using two different disease models and various immunological methods, we further characterized the conditions leading to Breg differentiation in humans. Here, we demonstrate that in humans CD40L determines whether IL-21 induces differentiation of B cells into plasma cells (CD40L presence) or into GrB+ Breg (CD40L absence), which can directly control T cell proliferation by GrB-dependent degradation of the T cell receptor z-chain. Furthermore, we show that GrB+ Breg are circulating at high frequencies in the peripheral blood of untreated, highly viremic HIV patients, but not in healthy subjects. Of note, HIV-infected CD4+ T cells express IL-21, but not CD40L, and induce a GrB+ regulatory phenotype in healthy third party B cells in vitro. Consequently, addition of CD40L multimers can compensate for this insufficient T helper cell function, resulting in increased plasma cell/Breg ratios. Moreover, we investigated a patient with a congenital defect of Nuclear-Factor-kappa-B-Essential-Modulator (NEMO), which is essential for normal CD40 signaling. Even in the presence of viral infections, when CD4+ T helper cells from such patients are highly activated with strong expression of IL-21, they are not able to establish sufficient antibody responses. Instead, we found this patient to almost exclusively harbor B cells with a regulatory phenotype including high basal levels of GrB. When untreated NEMO B cells were co-cultured with allogeneic T cells from a healthy third party donor, these T cells failed to proliferate and to survive in response to a 6-day stimulation with anti-CD3/CD28 antibodies, an effect not observed with B cells from healthy donors. Since NEMO B cells lack normal CD40 signaling, our findings unequivocally demonstrate that in contrast to murine Breg IL-21-dependent induction of human Breg can occur in a CD40-independent fashion.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling Blood |
spellingShingle | Jahrsdörfer, Bernd, Kaltenmeier, Christof, Gawanbacht, Ali, Beyer, Thamara, Schütz, Catharina, Hönig, Manfred, Kirchhoff, Frank, Schrezenmeier, Hubert, Blood, IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling, Cell Biology, Hematology, Immunology, Biochemistry |
title | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_full | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_fullStr | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_full_unstemmed | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_short | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
title_sort | il-21-mediated generation of human regulatory b cells occurs independently of cd40 signaling |
title_unstemmed | IL-21-Mediated Generation of Human Regulatory B Cells Occurs Independently of CD40 Signaling |
topic | Cell Biology, Hematology, Immunology, Biochemistry |
url | http://dx.doi.org/10.1182/blood.v124.21.1413.1413 |