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.

Subject headings

LANTBRUKSVETENSKAPER  -- Veterinärmedicin -- Patobiologi (hsv//swe)

AGRICULTURAL SCIENCES  -- Veterinary Science -- Pathobiology (hsv//eng)

Keyword

1-Phosphatidylinositol 3-Kinase

antagonists & inhibitors

metabolism

physiology

Adenine

administration & dosage

analogs & derivatives

Administration

Oral

Animals

Antibodies

Bacterial

biosynthesis

Autoantibodies

biosynthesis

B-Lymphocyte Subsets

drug effects

enzymology

immunology

microbiology

Cells

Cultured

Female

Gene Knock-In Techniques

Homeostasis

drug effects

immunology

Isoantibodies

biosynthesis

Mice

Mice

Inbred C57BL

Peritoneum

cytology

immunology

metabolism

Phosphorylation

drug effects

Proto-Oncogene Proteins c-akt

antagonists & inhibitors

metabolism

Quinazolines

administration & dosage

Rats

Rats

Inbred Lew

Spleen

cytology

drug effects

enzymology

immunology

Publication and Content Type

ref (subject category)

art (subject category)