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The Transcription Factor T-bet Resolves Memory B Cell Subsets with Distinct Tissue Distributions and Antibody Specificities in Mice and Humans

2020; Cell Press; Volume: 52; Issue: 5 Linguagem: Inglês

10.1016/j.immuni.2020.03.020

1097-4180

John L. Johnson, Rebecca L. Rosenthal, James J. Knox, Arpita Myles, Martin S. Naradikian, Joanna Madej, Mariya Kostiv, Aaron M. Rosenfeld, Wenzhao Meng, Shannon R. Christensen, Scott E. Hensley, Jonathan W. Yewdell, David H. Canaday, Jinfang Zhu, Adrian B. McDermott, Yoav Dori, Max Itkin, E. John Wherry, Norbert Pardi, Drew Weissman, Ali Naji, Eline T. Luning Prak, Michael R. Betts, Michael P. Cancro,

Immunotherapy and Immune Responses

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet+ and T-bet- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet- and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet- and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.