title: Btk regulates multiple stages in the development and survival of B-1 cells.
abstract: B-1 cells are important players in the first line of defense against pathogens. According to current models for the origin of B-1 cells, they either represent a separate lineage from conventional B-2 cells or differentiate from conventional B-2 cells via an intermediate, B-1(int), in response to positive selection by antigen. Here we show that Btk, a Tec family kinase that mediates B cell antigen receptor (BCR) signaling, is required at multiple stages of B-1 cell development. VH12 anti-phosphatidylcholine (PtC) IgH transgenic mice provide a model for the induced differentiation of B-1 cells. This transgene selects for PtC-reactive cells and induces them to adopt a B-1 phenotype. Both processes have been shown to depend on Btk. To determine whether this is secondary to a requirement for Btk in the development of mature B-2 cells, we crossed VH12 transgenic mice to mice expressing low levels of Btk. B-2 cell development occurs normally in Btk(lo) mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btk(lo) mice reveals that Btk regulates the B-1(int) to B-1 transition and/or the survival of splenic B-1 cells, in part via a mechanism independent of its role in BCR signaling. We also show that Btk mediates the survival of, and expression of IL-10 by, those B-1 cells that do develop and migrate to the peritoneum. Multiple roles for Btk in B-1 cell development and maintenance may explain the particular sensitivity of this population to mutations in components of Btk signaling pathways.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Contreras
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Halcomb
authors.forename: Lindsey
authors.initials: L
authors.lastname: Randle
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Hinman
authors.forename: Toni
authors.initials: T
authors.lastname: Gutierrez
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Clarke
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics; D002470:Cell Survival; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010537:Peritoneum / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology
chemical_list: D011947:Receptors, Antigen, B-Cell; D017455:Receptors, IgE; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase