Antigen presentation by B cells enables epitope spreading across an MHC barrier

Cecilia Fahlquist-Hagert, Thomas R. Wittenborn, Ewa Terczyńska-Dyla, Kristian Savstrup Kastberg, Emily Yang, Alysa Nicole Rallistan, Quinton Raymond Markett, Gudrun Winther, Sofie Fonager, Lasse F. Voss, Mathias K. Pedersen, Nina Campen, Alexey Ferapontov, Lisbeth Jensen, Jinrong Huang, John D. Nieland, Cees E. Poel, Johan Palmfeldt, Michael C. Carroll, Paul J. Utz, Yonglun Luo, Lin Lin and Søren E. Degn ()
Additional contact information
Cecilia Fahlquist-Hagert: Aarhus University
Thomas R. Wittenborn: Aarhus University
Ewa Terczyńska-Dyla: Aarhus University
Kristian Savstrup Kastberg: Aarhus University
Emily Yang: Stanford University
Alysa Nicole Rallistan: Stanford University
Quinton Raymond Markett: Stanford University
Gudrun Winther: Aarhus University
Sofie Fonager: Aarhus University
Lasse F. Voss: Aarhus University
Mathias K. Pedersen: Aarhus University
Nina Campen: Aarhus University
Alexey Ferapontov: Aarhus University
Lisbeth Jensen: Aarhus University
Jinrong Huang: Aarhus University
John D. Nieland: Aalborg University
Cees E. Poel: Boston Children’s Hospital
Johan Palmfeldt: Aarhus University
Michael C. Carroll: Boston Children’s Hospital
Paul J. Utz: Stanford University
Yonglun Luo: Aarhus University
Lin Lin: Aarhus University
Søren E. Degn: Aarhus University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Circumstantial evidence suggests that B cells may instruct T cells to break tolerance. Here, to test this hypothesis, we used a murine model in which a single B cell clone precipitates an autoreactive response resembling systemic lupus erythematosus (SLE). The initiating clone did not need to enter germinal centers to precipitate epitope spreading. Rather, it localized to extrafollicular splenic bridging channels early in the response. Autoantibody produced by the initiating clone was not sufficient to drive the autoreactive response. Subsequent epitope spreading depended on antigen presentation and was compartmentalized by major histocompatibility complex (MHC). B cells carrying two MHC haplotypes could bridge the MHC barrier between B cells that did not share MHC. Thus, B cells directly relay autoreactivity between two separate compartments of MHC-restricted T cells, leading to inclusion of distinct B cell populations in germinal centers. Our findings demonstrate that B cells initiate and propagate the autoimmune response.

Date: 2023
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DOI: 10.1038/s41467-023-42541-7

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