B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

Can Ulutekin; Edoardo Galli; Bettina Schreiner; Mohsen Khademi; Ilaria Callegari; Fredrik Piehl; Nicholas Sanderson; Daniel Kirschenbaum; Sarah Mundt; Massimo Filippi; Roberto Furlan; Tomas Olsson; Tobias Derfuss; Florian Ingelfinger; Burkhard Becher

doi:10.1016/j.xcrm.2023.101351

B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

Can Ulutekin, Edoardo Galli, Bettina Schreiner, Mohsen Khademi, Ilaria Callegari, Fredrik Piehl, Nicholas Sanderson, Daniel Kirschenbaum, Sarah Mundt, Massimo Filippi, Roberto Furlan, Tomas Olsson, Tobias Derfuss, Florian Ingelfinger, Burkhard Becher^*

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Whereas T cells are likely the main drivers of disease development, the striking efficacy of B cell-depleting therapies (BCDTs) underscore B cells’ involvement in disease progression. How B cells contribute to multiple sclerosis (MS) pathogenesis—and consequently the precise mechanism of action of BCDTs—remains elusive. Here, we analyze the impact of BCDTs on the immune landscape in patients with MS using high-dimensional single-cell immunophenotyping. Algorithm-guided analysis reveals a decrease in circulating T follicular helper-like (Tfh-like) cells alongside increases in CD27 expression in memory T helper cells and Tfh-like cells. Elevated CD27 indicates disrupted CD27/CD70 signaling, as sustained CD27 activation in T cells leads to its cleavage. Immunohistological analysis shows CD70-expressing B cells at MS lesion sites. These results suggest that the efficacy of BCDTs may partly hinge upon the disruption of Th cell and B cell interactions.

Original language	English
Article number	101351
Journal	Cell Reports Medicine
Volume	5
Issue number	1
DOIs	https://doi.org/10.1016/j.xcrm.2023.101351
Publication status	Published - 16 Jan 2024
Externally published	Yes

Bibliographical note

The authors would like to thank all the patients that participated in the study. We would also like to thank Catarina Raposo for the helpful review of the manuscript. This work received project funding from Roche Pharma (to B.B.), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program grant agreement no. 882424 (to B.B.), and the Swiss National Science Foundation (733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), as well as the Swiss MS Society Research grant (to F.I. and S.M.); F.I. received a PhD fellowship from the Studienstiftung des Deutschen Volkes. E.G. received grant support from the Research Funds for Excellent Junior Researcher of the University of Basel. T.O. has grant support from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, and the Margaretha af Ugglas Foundation.

Publisher Copyright:
© 2023 The Author(s)

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Cite this

Ulutekin, C., Galli, E., Schreiner, B., Khademi, M., Callegari, I., Piehl, F., Sanderson, N., Kirschenbaum, D., Mundt, S., Filippi, M., Furlan, R., Olsson, T., Derfuss, T., Ingelfinger, F., & Becher, B. (2024). B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis. Cell Reports Medicine, 5(1), Article 101351. https://doi.org/10.1016/j.xcrm.2023.101351

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title = "B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis",

abstract = "Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Whereas T cells are likely the main drivers of disease development, the striking efficacy of B cell-depleting therapies (BCDTs) underscore B cells{\textquoteright} involvement in disease progression. How B cells contribute to multiple sclerosis (MS) pathogenesis—and consequently the precise mechanism of action of BCDTs—remains elusive. Here, we analyze the impact of BCDTs on the immune landscape in patients with MS using high-dimensional single-cell immunophenotyping. Algorithm-guided analysis reveals a decrease in circulating T follicular helper-like (Tfh-like) cells alongside increases in CD27 expression in memory T helper cells and Tfh-like cells. Elevated CD27 indicates disrupted CD27/CD70 signaling, as sustained CD27 activation in T cells leads to its cleavage. Immunohistological analysis shows CD70-expressing B cells at MS lesion sites. These results suggest that the efficacy of BCDTs may partly hinge upon the disruption of Th cell and B cell interactions.",

author = "Can Ulutekin and Edoardo Galli and Bettina Schreiner and Mohsen Khademi and Ilaria Callegari and Fredrik Piehl and Nicholas Sanderson and Daniel Kirschenbaum and Sarah Mundt and Massimo Filippi and Roberto Furlan and Tomas Olsson and Tobias Derfuss and Florian Ingelfinger and Burkhard Becher",

note = "The authors would like to thank all the patients that participated in the study. We would also like to thank Catarina Raposo for the helpful review of the manuscript. This work received project funding from Roche Pharma (to B.B.), the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program grant agreement no. 882424 (to B.B.), and the Swiss National Science Foundation (733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), as well as the Swiss MS Society Research grant (to F.I. and S.M.); F.I. received a PhD fellowship from the Studienstiftung des Deutschen Volkes. E.G. received grant support from the Research Funds for Excellent Junior Researcher of the University of Basel. T.O. has grant support from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, and the Margaretha af Ugglas Foundation. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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AU - Ulutekin, Can

AU - Galli, Edoardo

AU - Schreiner, Bettina

AU - Khademi, Mohsen

AU - Callegari, Ilaria

AU - Piehl, Fredrik

AU - Sanderson, Nicholas

AU - Kirschenbaum, Daniel

AU - Mundt, Sarah

AU - Filippi, Massimo

AU - Furlan, Roberto

AU - Olsson, Tomas

AU - Derfuss, Tobias

AU - Ingelfinger, Florian

AU - Becher, Burkhard

N1 - The authors would like to thank all the patients that participated in the study. We would also like to thank Catarina Raposo for the helpful review of the manuscript. This work received project funding from Roche Pharma (to B.B.), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program grant agreement no. 882424 (to B.B.), and the Swiss National Science Foundation (733 310030_170320, 310030_188450 and CRSII5_183478 to B.B.), as well as the Swiss MS Society Research grant (to F.I. and S.M.); F.I. received a PhD fellowship from the Studienstiftung des Deutschen Volkes. E.G. received grant support from the Research Funds for Excellent Junior Researcher of the University of Basel. T.O. has grant support from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Brain Foundation, and the Margaretha af Ugglas Foundation. Publisher Copyright: © 2023 The Author(s)

PY - 2024/1/16

Y1 - 2024/1/16

N2 - Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Whereas T cells are likely the main drivers of disease development, the striking efficacy of B cell-depleting therapies (BCDTs) underscore B cells’ involvement in disease progression. How B cells contribute to multiple sclerosis (MS) pathogenesis—and consequently the precise mechanism of action of BCDTs—remains elusive. Here, we analyze the impact of BCDTs on the immune landscape in patients with MS using high-dimensional single-cell immunophenotyping. Algorithm-guided analysis reveals a decrease in circulating T follicular helper-like (Tfh-like) cells alongside increases in CD27 expression in memory T helper cells and Tfh-like cells. Elevated CD27 indicates disrupted CD27/CD70 signaling, as sustained CD27 activation in T cells leads to its cleavage. Immunohistological analysis shows CD70-expressing B cells at MS lesion sites. These results suggest that the efficacy of BCDTs may partly hinge upon the disruption of Th cell and B cell interactions.

AB - Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Whereas T cells are likely the main drivers of disease development, the striking efficacy of B cell-depleting therapies (BCDTs) underscore B cells’ involvement in disease progression. How B cells contribute to multiple sclerosis (MS) pathogenesis—and consequently the precise mechanism of action of BCDTs—remains elusive. Here, we analyze the impact of BCDTs on the immune landscape in patients with MS using high-dimensional single-cell immunophenotyping. Algorithm-guided analysis reveals a decrease in circulating T follicular helper-like (Tfh-like) cells alongside increases in CD27 expression in memory T helper cells and Tfh-like cells. Elevated CD27 indicates disrupted CD27/CD70 signaling, as sustained CD27 activation in T cells leads to its cleavage. Immunohistological analysis shows CD70-expressing B cells at MS lesion sites. These results suggest that the efficacy of BCDTs may partly hinge upon the disruption of Th cell and B cell interactions.

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ER -

B cell depletion attenuates CD27 signaling of T helper cells in multiple sclerosis

Abstract

Bibliographical note

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