Protein kinase Cdelta controls self-antigen-induced B-cell tolerance.
Interaction of a B cell expressing self-specific B-cell antigen receptor (BCR) with an auto-antigen results in either clonal deletion or functional inactivation. Both of these processes lead to B-cell tolerance and are essential for the prevention of auto-immune diseases. Whereas clonal deletion results in the death of developing autoreactive B cells, functional inactivation of self-reactive B lymphocytes leads to complex changes in the phenotype of peripheral B cells, described collectively as anergy. Here we demonstrate that deficiency in protein kinase Cdelta (PKC-delta) prevents B-cell tolerance, and allows maturation and terminal differentiation of self-reactive B cells in the presence of the tolerizing antigen. The importance of PKC-delta in B-cell tolerance is further underscored by the appearance of autoreactive anti-DNA and anti-nuclear antibodies in the serum of PKC-delta-deficient mice. As deficiency of PKC-delta does not affect BCR-mediated B-cell activation in vitro and in vivo, our data suggest a selective and essential role of PKC-delta in tolerogenic, but not immunogenic, B-cell responses.
Mecklenbräuker
Ingrid
I
Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, New York 10021, USA.
Saijo
Kaoru
K
Zheng
Nai-Ying
NY
Leitges
Michael
M
Tarakhovsky
Alexander
A
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051940:B7-2 Antigen; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002454:Cell Differentiation; D017635:Clonal Anergy / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D017353:Gene Deletion; D007108:Immune Tolerance / Q000276:immunology*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051745:Protein Kinase C-delta; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D001324:Autoantigens; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007527:Isoenzymes; D008562:Membrane Glycoproteins; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium