B-1a Cells Acquire Their Unique Characteristics by Bypassing the pre-BCR Selection Stage

Nat Commun. 2019 Oct 18;10(1):4768. doi: 10.1038/s41467-019-12824-z.

Abstract

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Bone Marrow / immunology
  • Bone Marrow / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Immunoglobulin Light Chains, Surrogate / genetics
  • Immunoglobulin Light Chains, Surrogate / immunology
  • Immunoglobulin Light Chains, Surrogate / metabolism
  • Liver / embryology
  • Liver / immunology
  • Liver / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pre-B Cell Receptors / genetics
  • Pre-B Cell Receptors / immunology*
  • Pre-B Cell Receptors / metabolism
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / immunology
  • Receptors, Interleukin-7 / metabolism
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology
  • STAT5 Transcription Factor / metabolism

Substances

  • Immunoglobulin Light Chains, Surrogate
  • Pre-B Cell Receptors
  • Receptors, Antigen, B-Cell
  • Receptors, Interleukin-7
  • STAT5 Transcription Factor