The expansion of human T-bethighCD21low B cells is T cell dependent

Baerbel Keller; Valentina Strohmeier; Ina Harder; Susanne Unger; Kathryn J. Payne; Geoffroy Andrieux; Melanie Boerries; Peter Tobias Felixberger; Jonathan J.M. Landry; Alexandra Nieters; Anne Rensing-Ehl; Ulrich Salzer; Natalie Frede; Susanne Usadel; Roland Elling; Carsten Speckmann; Ina Hainmann; Elizabeth Ralph; Kimberly Gilmour; Marjolein W.J. Wentink; Mirjam van der Burg; Hye Sun Kuehn; Sergio D. Rosenzweig; Uwe Kölsch; Horst von Bernuth; Petra Kaiser-Labusch; Florian Gothe; Sophie Hambleton; Alexandru Daniel Vlagea; Ana Garcia Garcia; Laia Alsina; Gašper Markelj; Tadej Avcin; Julia Vasconcelos; Margarida Guedes; Jing Ya Ding; Cheng Lung Ku; Bella Shadur; Danielle T. Avery; Nils Venhoff; Jens Thiel; Heiko Becker; Lucía Erazo-Borrás; Claudia Milena Trujillo-Vargas; José Luis Franco; Claire Fieschi; Satoshi Okada; Paul E. Gray; Gulbu Uzel; Jean Laurent Casanova; Manfred Fliegauf; Bodo Grimbacher; Hermann Eibel; Stephan Ehl; Reinhard E. Voll; Marta Rizzi; Polina Stepensky; Vladimir Benes; Cindy S. Ma; Claudia Bossen; Stuart G. Tangye; Klaus Warnatz

doi:10.1126/sciimmunol.abh0891

The expansion of human T-bet^highCD21^low B cells is T cell dependent

Baerbel Keller^*, Valentina Strohmeier, Ina Harder, Susanne Unger, Kathryn J. Payne, Geoffroy Andrieux, Melanie Boerries, Peter Tobias Felixberger, Jonathan J.M. Landry, Alexandra Nieters, Anne Rensing-Ehl, Ulrich Salzer, Natalie Frede, Susanne Usadel, Roland Elling, Carsten Speckmann, Ina Hainmann, Elizabeth Ralph, Kimberly Gilmour, Marjolein W.J. WentinkMirjam van der Burg, Hye Sun Kuehn, Sergio D. Rosenzweig, Uwe Kölsch, Horst von Bernuth, Petra Kaiser-Labusch, Florian Gothe, Sophie Hambleton, Alexandru Daniel Vlagea, Ana Garcia Garcia, Laia Alsina, Gašper Markelj, Tadej Avcin, Julia Vasconcelos, Margarida Guedes, Jing Ya Ding, Cheng Lung Ku, Bella Shadur, Danielle T. Avery, Nils Venhoff, Jens Thiel, Heiko Becker, Lucía Erazo-Borrás, Claudia Milena Trujillo-Vargas, José Luis Franco, Claire Fieschi, Satoshi Okada, Paul E. Gray, Gulbu Uzel, Jean Laurent Casanova, Manfred Fliegauf, Bodo Grimbacher, Hermann Eibel, Stephan Ehl, Reinhard E. Voll, Marta Rizzi, Polina Stepensky, Vladimir Benes, Cindy S. Ma, Claudia Bossen, Stuart G. Tangye, Klaus Warnatz

^*Corresponding author for this work

Immunology

Research output: Contribution to journal › Article › Academic › peer-review

105 Citations (Scopus)

Abstract

Accumulation of human CD21^low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21^low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bet^highCD21^low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21^low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bet^highCD21^low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21^low B cell proportions. The expansion of human T-bet^highCD21^low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bet^highCD21^low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

Original language	English
Article number	eabh0891
Journal	Science immunology
Volume	6
Issue number	64
DOIs	https://doi.org/10.1126/sciimmunol.abh0891
Publication status	Published - 8 Oct 2021

Bibliographical note

Acknowledgments:
We would like to thank the Advanced Diagnostics Unit of the CCI, the AWIS cohort, and N. Langer for excellent technical support; the physicians and nurses of the CCI, the Department of Rheumatology and Clinical Immunology, and the Infektiologikum Freiburg for patient care and support; and the Lighthouse Core Facility of the University Medical Center Freiburg for cell sorting. The Galaxy server that was used for some calculations is in part funded by Collaborative Research Centre 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and German Federal Ministry of Education and Research [BMBF grants 031 A538A/ A538C RBC, 031L0101B/031L0101C de.NBI-epi, 031L0106 de.STAIR (de.NBI)]. Samples for this project were obtained from the CCI-Biobank and the Immunologisch-Rheumatologische (IR) Biobank, both are partner biobanks of the University Medical Center Freiburg and Medical Faculty “Center for Biobanking–FREEZE”. This work was supported by grants from the German Research Foundation TRR130 TP07 and WA 1597/4-2 and from the German Federal Ministry of Education and Research BMBF 01EO1303 and BMBF “Netzwerke Seltener Erkrankungen,” GAIN_01GM1910A to K.W. S.G.T. was supported by Investigator and Program grants awarded by the National Health and Medical Research Council of Australia. R.E.V. received funding from the German Research Foundation TRR130 TP12. M.B. was supported by the German Research Foundation SFB1160/2 Z02. C.S.M. was supported by the Early-Mid Career Research Fellowship from the New South Wales Government. K.G. received funding from the NIHR BRC at Great Ormond Street Hospital. H.B. was supported by the Boehringer Ingelheim Stiftung Exploration Grant. B.G. received funding from the BMBF Netzwerke Seltener Erkrankungen, GAIN_01GM1910A and the German Research Foundation RESIST–EXC 2155–project ID 390874280, SFB1160/2_B5, GR1617/14-1/iPAD, and CIBSS–EXC-2189–project ID 390939984.

Publisher Copyright: Copyright © 2021 The Authors,

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Keller, B., Strohmeier, V., Harder, I., Unger, S., Payne, K. J., Andrieux, G., Boerries, M., Felixberger, P. T., Landry, J. J. M., Nieters, A., Rensing-Ehl, A., Salzer, U., Frede, N., Usadel, S., Elling, R., Speckmann, C., Hainmann, I., Ralph, E., Gilmour, K., ... Warnatz, K. (2021). The expansion of human T-bet^highCD21^low B cells is T cell dependent. Science immunology, 6(64), Article eabh0891. https://doi.org/10.1126/sciimmunol.abh0891

@article{3752b4a939d34276bd25b2fbb733919c,

title = "The expansion of human T-bethighCD21low B cells is T cell dependent",

abstract = "Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.",

author = "Baerbel Keller and Valentina Strohmeier and Ina Harder and Susanne Unger and Payne, {Kathryn J.} and Geoffroy Andrieux and Melanie Boerries and Felixberger, {Peter Tobias} and Landry, {Jonathan J.M.} and Alexandra Nieters and Anne Rensing-Ehl and Ulrich Salzer and Natalie Frede and Susanne Usadel and Roland Elling and Carsten Speckmann and Ina Hainmann and Elizabeth Ralph and Kimberly Gilmour and Wentink, {Marjolein W.J.} and {van der Burg}, Mirjam and Kuehn, {Hye Sun} and Rosenzweig, {Sergio D.} and Uwe K{\"o}lsch and {von Bernuth}, Horst and Petra Kaiser-Labusch and Florian Gothe and Sophie Hambleton and Vlagea, {Alexandru Daniel} and Garcia, {Ana Garcia} and Laia Alsina and Ga{\v s}per Markelj and Tadej Avcin and Julia Vasconcelos and Margarida Guedes and Ding, {Jing Ya} and Ku, {Cheng Lung} and Bella Shadur and Avery, {Danielle T.} and Nils Venhoff and Jens Thiel and Heiko Becker and Luc{\'i}a Erazo-Borr{\'a}s and Trujillo-Vargas, {Claudia Milena} and Franco, {Jos{\'e} Luis} and Claire Fieschi and Satoshi Okada and Gray, {Paul E.} and Gulbu Uzel and Casanova, {Jean Laurent} and Manfred Fliegauf and Bodo Grimbacher and Hermann Eibel and Stephan Ehl and Voll, {Reinhard E.} and Marta Rizzi and Polina Stepensky and Vladimir Benes and Ma, {Cindy S.} and Claudia Bossen and Tangye, {Stuart G.} and Klaus Warnatz",

note = "Acknowledgments: We would like to thank the Advanced Diagnostics Unit of the CCI, the AWIS cohort, and N. Langer for excellent technical support; the physicians and nurses of the CCI, the Department of Rheumatology and Clinical Immunology, and the Infektiologikum Freiburg for patient care and support; and the Lighthouse Core Facility of the University Medical Center Freiburg for cell sorting. The Galaxy server that was used for some calculations is in part funded by Collaborative Research Centre 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and German Federal Ministry of Education and Research [BMBF grants 031 A538A/ A538C RBC, 031L0101B/031L0101C de.NBI-epi, 031L0106 de.STAIR (de.NBI)]. Samples for this project were obtained from the CCI-Biobank and the Immunologisch-Rheumatologische (IR) Biobank, both are partner biobanks of the University Medical Center Freiburg and Medical Faculty “Center for Biobanking–FREEZE”. This work was supported by grants from the German Research Foundation TRR130 TP07 and WA 1597/4-2 and from the German Federal Ministry of Education and Research BMBF 01EO1303 and BMBF “Netzwerke Seltener Erkrankungen,” GAIN_01GM1910A to K.W. S.G.T. was supported by Investigator and Program grants awarded by the National Health and Medical Research Council of Australia. R.E.V. received funding from the German Research Foundation TRR130 TP12. M.B. was supported by the German Research Foundation SFB1160/2 Z02. C.S.M. was supported by the Early-Mid Career Research Fellowship from the New South Wales Government. K.G. received funding from the NIHR BRC at Great Ormond Street Hospital. H.B. was supported by the Boehringer Ingelheim Stiftung Exploration Grant. B.G. received funding from the BMBF Netzwerke Seltener Erkrankungen, GAIN_01GM1910A and the German Research Foundation RESIST–EXC 2155–project ID 390874280, SFB1160/2_B5, GR1617/14-1/iPAD, and CIBSS–EXC-2189–project ID 390939984. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors,",

year = "2021",

month = oct,

day = "8",

doi = "10.1126/sciimmunol.abh0891",

language = "English",

volume = "6",

journal = "Science immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "64",

}

Keller, B, Strohmeier, V, Harder, I, Unger, S, Payne, KJ, Andrieux, G, Boerries, M, Felixberger, PT, Landry, JJM, Nieters, A, Rensing-Ehl, A, Salzer, U, Frede, N, Usadel, S, Elling, R, Speckmann, C, Hainmann, I, Ralph, E, Gilmour, K, Wentink, MWJ, van der Burg, M, Kuehn, HS, Rosenzweig, SD, Kölsch, U, von Bernuth, H, Kaiser-Labusch, P, Gothe, F, Hambleton, S, Vlagea, AD, Garcia, AG, Alsina, L, Markelj, G, Avcin, T, Vasconcelos, J, Guedes, M, Ding, JY, Ku, CL, Shadur, B, Avery, DT, Venhoff, N, Thiel, J, Becker, H, Erazo-Borrás, L, Trujillo-Vargas, CM, Franco, JL, Fieschi, C, Okada, S, Gray, PE, Uzel, G, Casanova, JL, Fliegauf, M, Grimbacher, B, Eibel, H, Ehl, S, Voll, RE, Rizzi, M, Stepensky, P, Benes, V, Ma, CS, Bossen, C, Tangye, SG & Warnatz, K 2021, 'The expansion of human T-bet^highCD21^low B cells is T cell dependent', Science immunology, vol. 6, no. 64, eabh0891. https://doi.org/10.1126/sciimmunol.abh0891

TY - JOUR

T1 - The expansion of human T-bethighCD21low B cells is T cell dependent

AU - Keller, Baerbel

AU - Strohmeier, Valentina

AU - Harder, Ina

AU - Unger, Susanne

AU - Payne, Kathryn J.

AU - Andrieux, Geoffroy

AU - Boerries, Melanie

AU - Felixberger, Peter Tobias

AU - Landry, Jonathan J.M.

AU - Nieters, Alexandra

AU - Rensing-Ehl, Anne

AU - Salzer, Ulrich

AU - Frede, Natalie

AU - Usadel, Susanne

AU - Elling, Roland

AU - Speckmann, Carsten

AU - Hainmann, Ina

AU - Ralph, Elizabeth

AU - Gilmour, Kimberly

AU - Wentink, Marjolein W.J.

AU - van der Burg, Mirjam

AU - Kuehn, Hye Sun

AU - Rosenzweig, Sergio D.

AU - Kölsch, Uwe

AU - von Bernuth, Horst

AU - Kaiser-Labusch, Petra

AU - Gothe, Florian

AU - Hambleton, Sophie

AU - Vlagea, Alexandru Daniel

AU - Garcia, Ana Garcia

AU - Alsina, Laia

AU - Markelj, Gašper

AU - Avcin, Tadej

AU - Vasconcelos, Julia

AU - Guedes, Margarida

AU - Ding, Jing Ya

AU - Ku, Cheng Lung

AU - Shadur, Bella

AU - Avery, Danielle T.

AU - Venhoff, Nils

AU - Thiel, Jens

AU - Becker, Heiko

AU - Erazo-Borrás, Lucía

AU - Trujillo-Vargas, Claudia Milena

AU - Franco, José Luis

AU - Fieschi, Claire

AU - Okada, Satoshi

AU - Gray, Paul E.

AU - Uzel, Gulbu

AU - Casanova, Jean Laurent

AU - Fliegauf, Manfred

AU - Grimbacher, Bodo

AU - Eibel, Hermann

AU - Ehl, Stephan

AU - Voll, Reinhard E.

AU - Rizzi, Marta

AU - Stepensky, Polina

AU - Benes, Vladimir

AU - Ma, Cindy S.

AU - Bossen, Claudia

AU - Tangye, Stuart G.

AU - Warnatz, Klaus

N1 - Acknowledgments: We would like to thank the Advanced Diagnostics Unit of the CCI, the AWIS cohort, and N. Langer for excellent technical support; the physicians and nurses of the CCI, the Department of Rheumatology and Clinical Immunology, and the Infektiologikum Freiburg for patient care and support; and the Lighthouse Core Facility of the University Medical Center Freiburg for cell sorting. The Galaxy server that was used for some calculations is in part funded by Collaborative Research Centre 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and German Federal Ministry of Education and Research [BMBF grants 031 A538A/ A538C RBC, 031L0101B/031L0101C de.NBI-epi, 031L0106 de.STAIR (de.NBI)]. Samples for this project were obtained from the CCI-Biobank and the Immunologisch-Rheumatologische (IR) Biobank, both are partner biobanks of the University Medical Center Freiburg and Medical Faculty “Center for Biobanking–FREEZE”. This work was supported by grants from the German Research Foundation TRR130 TP07 and WA 1597/4-2 and from the German Federal Ministry of Education and Research BMBF 01EO1303 and BMBF “Netzwerke Seltener Erkrankungen,” GAIN_01GM1910A to K.W. S.G.T. was supported by Investigator and Program grants awarded by the National Health and Medical Research Council of Australia. R.E.V. received funding from the German Research Foundation TRR130 TP12. M.B. was supported by the German Research Foundation SFB1160/2 Z02. C.S.M. was supported by the Early-Mid Career Research Fellowship from the New South Wales Government. K.G. received funding from the NIHR BRC at Great Ormond Street Hospital. H.B. was supported by the Boehringer Ingelheim Stiftung Exploration Grant. B.G. received funding from the BMBF Netzwerke Seltener Erkrankungen, GAIN_01GM1910A and the German Research Foundation RESIST–EXC 2155–project ID 390874280, SFB1160/2_B5, GR1617/14-1/iPAD, and CIBSS–EXC-2189–project ID 390939984. Publisher Copyright: Copyright © 2021 The Authors,

PY - 2021/10/8

Y1 - 2021/10/8

N2 - Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

AB - Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

UR - http://www.scopus.com/inward/record.url?scp=85116879703&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.abh0891

DO - 10.1126/sciimmunol.abh0891

M3 - Article

C2 - 34623902

AN - SCOPUS:85116879703

SN - 2470-9468

VL - 6

JO - Science immunology

JF - Science immunology

IS - 64

M1 - eabh0891

ER -