Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses

Abstract

B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ 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 p110δ enzymatic activity, we show that p110δ 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, p110δ 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 p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.

Selective Inhibition of Phosphoinositide 3-Kinase p110α Preserves Lymphocyte Function*

“…Similarly, pharmacological inhibition of p110␦ with IC87114 in vivo causes aberrant localization of MZ B cells (28). In accord, we detected fewer MZ B cells (IgM hi IgD lo ) in spleen sections of mice treated with IC87114 or the pan class I inhibitor GDC-0941 (Fig.…”

“…Genetic studies in mice suggest that a central signaling pathway governing MZ B cell development is initiated by CD19 on the cell surface, which signals via PI3K-p110␦ and AKT to suppress the transcription factor Foxo1 (40). Pharmacological inhibition of p110␦ using IC87114 reduces MZ B cell numbers but also disrupts their localization, with IgM hi /IgD lo B cells moving into the follicles (28). This is consistent with other data showing that chemokine responses in MZ B cells are largely dependent on the p110␦ isoform (28).…”

“…Disruption of the MZ B cell subset is now recognized as a biomarker of p110␦ inhibition in mice (28,40). Genetic studies in mice suggest that a central signaling pathway governing MZ B cell development is initiated by CD19 on the cell surface, which signals via PI3K-p110␦ and AKT to suppress the transcription factor Foxo1 (40).…”

“…As another means to inhibit p110␤, we used the compound MLN1316, a dual p110␣/p110␤ inhibitor that is highly selective relative to p110␦ and p110␥ (Table 1). We used IC87114 as a p110␦ inhibitor (27)(28)(29). To inhibit all class I isoforms, we used the two compounds GDC-0941 (11,30,31) and ZSTK474 (32,33).…”

“…For treatments with GDC-0941 or MLN1117, we used doses and formulations shown to provide anti-cancer efficacy in solid tumor xenograft models (31). 3 For treatment with IC87114, we used a dose and treatment protocol previously shown to reduce MZ B cell numbers in mice (28). Daily treatment with MLN1117, IC87114, or GDC-0941 did not alter the percentages or numbers of T cells, and did not affect the ratio of CD4 and CD8 T cells relative to vehicle-treated controls (data not shown).…”