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

Cell Rep Med. 2024 Jan 16;5(1):101351. doi: 10.1016/j.xcrm.2023.101351. Epub 2023 Dec 21.

Authors

Affiliations

¹ Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
² Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Multiple Sclerosis Center, Neurologic Clinic and Policlinic, Department of Biomedicine and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland.
³ Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland; Department of Neurology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
⁴ Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Visionsgatan 18A, 171 76 Stockholm, Sweden.
⁵ Multiple Sclerosis Center, Neurologic Clinic and Policlinic, Department of Biomedicine and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland.
⁶ Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
⁷ Neurology Unit, Neurorehabilitation Unit, Neurophysiology Service, and Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Via Olgettina n. 60 - 20132, Italy; Vita-Salute San Raffaele University, Milan, Via Olgettina n. 60 - 20132, Italy.
⁸ Clinical Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina n. 60 - 20132, Milan, Italy.
⁹ Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Electronic address: becher@immunology.uzh.ch.

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.

Keywords: B cell depletion; CD27; CD4(+) T cells; CD70; mass cytometry; multiple sclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Lymphocytes
Humans
Immunophenotyping
Multiple Sclerosis* / pathology
Signal Transduction
T-Lymphocytes, Helper-Inducer