TY - JOUR
T1 - BOB.1 controls memory B-cell fate in the germinal center reaction
AU - Levels, Maartje J.
AU - Fehres, Cynthia M.
AU - van Baarsen, Lisa G. M.
AU - van Uden, Nathalie O. P.
AU - Germar, Kristine
AU - O'Toole, Tom G.
AU - Blijdorp, Iris C. J.
AU - Semmelink, Johanna F.
AU - Doorenspleet, Marieke E.
AU - Bakker, Arjen Q.
AU - Krasavin, Mikhail
AU - Tomilin, Alexey
AU - Brouard, Sophie
AU - Spits, Hergen
AU - Baeten, Dominique L. P.
AU - Yeremenko, Nataliya G.
PY - 2019
Y1 - 2019
N2 - During T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical autoimmune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination.
AB - During T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical autoimmune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85067009896&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31053401
U2 - https://doi.org/10.1016/j.jaut.2019.04.011
DO - https://doi.org/10.1016/j.jaut.2019.04.011
M3 - Article
C2 - 31053401
SN - 0896-8411
VL - 101
SP - 131
EP - 144
JO - Journal of autoimmunity
JF - Journal of autoimmunity
ER -