T‐bet‐expressing B cells contribute to the autoreactive plasma cell pool in Lyn‐/‐ mice

• Published in: European journal of immunology Vol. 53; no. 8; pp. e2250300 - n/a
• Main Authors: Ottens, Kristina, Schneider, Jalyn, Satterthwaite, Anne B.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.08.2023
• Subjects: Animals; Antigens; Autoantibodies; autoantibody; Autoimmune diseases; Cell activation; Cell differentiation; Cell fate; Class switching; Immunoglobulin G; Immunoglobulin M; Lupus; Lupus Erythematosus, Systemic; Lymphocytes B; Lyn; Mice; plasma cell; Plasma Cells; Protein-tyrosine kinase; Spleen; src-Family Kinases - genetics; Systemic lupus erythematosus; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; T‐bet; Lyn; autoantibody; T-bet; lupus; plasma cell
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.202250300

Systemic Lupus Erythematosus (SLE) is characterized by pathogenic autoantibodies against nucleic acid‐containing antigens. Understanding which B‐cell subsets give rise to these autoantibodies may reveal therapeutic approaches for SLE that spare protective responses. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus‐like autoimmune diseases characterized by increased autoreactive plasma cells (PCs). We used a fate‐mapping strategy to determine the contribution of T‐bet+ B cells, a subset thought to be pathogenic in lupus, to the accumulation of PCs and autoantibodies in Lyn‐/‐ mice. Approximately, 50% of splenic PCs in Lyn‐/‐ mice originated from T‐bet+ cells, a significant increase compared to WT mice. In vitro, splenic PCs derived from T‐bet+ B cells secreted both IgM and IgG anti‐dsDNA antibodies. To determine the role of these cells in autoantibody production in vivo, we prevented T‐bet+ B cells from differentiating into PCs or class switching in Lyn‐/‐ mice. This resulted in a partial reduction in splenic PCs and anti‐dsDNA IgM and complete abrogation of anti‐dsDNA IgG. Thus, T‐bet+ B cells make an important contribution to the autoreactive PC pool in Lyn‐/‐ mice. Lyn‐/‐ mice, a model of lupus, have increased T‐bet+ follicular B cells and age‐associated B cells. Plasma cells derived from T‐bet‐expressing B cells (marked by a Tbx21‐cre.tomato reporter) accumulate in the spleens of Lyn‐/‐ mice and give rise to some IgM, and the majority of IgG, anti‐dsDNA autoantibodies.