TY - JOUR
T1 - Btk regulates multiple stages in the development and survival of B-1 cells
AU - Contreras, Cristina M.
AU - Halcomb, Kristina E.
AU - Randle, Lindsey
AU - Hinman, Rochelle M.
AU - Gutierrez, Toni
AU - Clarke, Stephen H.
AU - Satterthwaite, Anne B.
N1 - Funding Information:
We thank Dr. Clifford Lowell for the Lyn−/− mice, Angela Mobley for flow cytometry, Kelvin Hsu for sequencing, and Heather Wright, Colin Court, and Sandirai Musuka for mouse genotyping. This work was supported by grants from the NIH (R01 AI049248 to A.S., R01 AI29576 and R01 AI43587 to S.C., and T32 AI 005284-28 to R.H.) and the Texas Higher Education Coordinating Board ARP/ATP program (010019-0074-2001 to A.S.). C.C. was supported in part by the UT Southwestern SURF Program. A.S. is a Southwestern Medical Foundation Scholar in Biomedical Research.
PY - 2007/4
Y1 - 2007/4
N2 - 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-1int, 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 Btklo mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btklo mice reveals that Btk regulates the B-1int 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.
AB - 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-1int, 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 Btklo mice despite reduced responsiveness to BCR crosslinking. Analysis of VH12.Btklo mice reveals that Btk regulates the B-1int 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.
KW - B cell development
KW - BCR signaling
KW - IL-10
KW - Lyn
KW - Phosphatidylcholine
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UR - http://www.scopus.com/inward/citedby.url?scp=33846903332&partnerID=8YFLogxK
U2 - 10.1016/j.molimm.2006.11.023
DO - 10.1016/j.molimm.2006.11.023
M3 - Article
C2 - 17207856
AN - SCOPUS:33846903332
SN - 0161-5890
VL - 44
SP - 2719
EP - 2728
JO - Molecular Immunology
JF - Molecular Immunology
IS - 10
ER -