A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells

Immunity. 2016 Jan 19;44(1):116-130. doi: 10.1016/j.immuni.2015.12.004. Epub 2016 Jan 12.


There is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • B-Lymphocyte Subsets / cytology*
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • Cell Differentiation / immunology*
  • Cell Separation
  • Enzyme-Linked Immunospot Assay
  • Flow Cytometry
  • Germinal Center / cytology
  • Germinal Center / immunology*
  • Immunity, Humoral / immunology
  • Immunohistochemistry
  • Immunologic Memory / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Plasma Cells / cytology*
  • Plasma Cells / immunology
  • Time Factors