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

Immunity. 2020 May 19;52(5):842-855.e6. doi: 10.1016/j.immuni.2020.03.020. Epub 2020 Apr 29.


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.

Keywords: Age-associated B cells; B cell memory; BCR sequencing; Humoral immunity; T-bet(+) B cells; antibody; hemagglutinin stalk; immune repertoire profiling; influenza; tissue-resident.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibody Specificity / immunology*
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • HIV Antibodies / immunology
  • Humans
  • Immunologic Memory / immunology*
  • Influenza A virus / immunology
  • Influenza A virus / physiology
  • Influenza, Human / immunology
  • Influenza, Human / virology
  • Mice
  • Organ Specificity / immunology*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology*
  • T-Box Domain Proteins / metabolism


  • Antibodies, Neutralizing
  • HIV Antibodies
  • T-Box Domain Proteins
  • T-box transcription factor TBX21