The calcineurin phosphatase complex modulates immunogenic B cell responses.
A series of signal-directed transitions regulates the development of distinct populations of self-tolerant B cells and ultimately the production of antibody-producing plasma cells. We studied the role of calcineurin/NFAT signaling in B cells by deleting the regulatory b1 subunit of calcineurin specifically in B cells. Follicular (FO) and marginal zone (MZ) B cells develop normally in these mice, but B1 cell numbers are reduced. In vitro, calcineurin b1-deficient B cells have a cell-intrinsic proliferation defect downstream of the B cell receptor. These mice have higher total serum IgM despite the absence of B1 cells and have enhanced T cell-independent-1 responses. Conversely, mice with calcineurin b1-deficient B cells develop larger germinal centers and have reduced plasma cell development and antigen-specific antibody production during T cell-dependent immune responses. By several different criteria, calcineurin is dispensable for B cell tolerance, indicating that this phosphatase complex modulates immunogenic, but not tolerogenic, responses in vivo.
Winslow
Monte M
MM
Program in Immunology, Stanford University, Stanford, California 94305, USA.
Gallo
Elena M
EM
Neilson
Joel R
JR
Crabtree
Gerald R
GR
D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D018858:Germinal Center / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D012469:Salivary Glands / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000955:Antigens, T-Independent; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium