Phosphoinositide 3-kinase p110 delta regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses.
B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the delta isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110delta enzymatic activity, we show that p110delta is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110delta activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110delta activity. Finally, we show that the in vivo production of natural Abs requires p110delta and that p110delta inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110delta may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.
Department of Microbiology and Immunology, Infection, Inflammation, and Immunity (I(3)) and CELL Research Groups, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Caylib A
CA
Durand
Karsten
K
Hartvigsen
Linda
L
Fogelstrand
Shin
S
Kim
Sally
S
Iritani
Bart
B
Vanhaesebroeck
Joseph L
JL
Witztum
Kamal D
KD
Puri
Michael R
MR
Gold
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D055879:Gene Knock-In Techniques; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D010537:Peritoneum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D000225:Adenine; D000907:Antibodies, Bacterial; D001323:Autoantibodies; D058534:Class I Phosphatidylinositol 3-Kinases; D007518:Isoantibodies; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C477872:IC 87114; C421683:Pik3cd protein, mouse