ABSTRACT
The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.
Subject(s)
Adenosine Deaminase/deficiency , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/etiology , Intercellular Signaling Peptides and Proteins/deficiency , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/genetics , Adenosine Deaminase/blood , Antiviral Agents/therapeutic use , Biomarkers , Biopsy , Child , DNA Mutational Analysis , Disease Management , Disease Susceptibility , Epstein-Barr Virus Infections/drug therapy , Female , Hematopoietic Stem Cell Transplantation , Humans , Intercellular Signaling Peptides and Proteins/blood , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/therapy , Siblings , Symptom Assessment , Tomography, X-Ray Computed , Treatment Outcome , Exome SequencingABSTRACT
Over the past two decades, new insights have positioned phosphoinositide 3-kinase-γ (PI3Kγ) as a context-dependent modulator of immunity and inflammation. Recent advances in protein structure determination and drug development have allowed for generation of highly specific PI3Kγ inhibitors, with the first now in clinical trials for several oncology indications. Recently, a monogenic immune disorder caused by PI3Kγ deficiency was discovered in humans and modelled in mice. Human inactivated PI3Kγ syndrome confirms the immunomodulatory roles of PI3Kγ and strengthens newly defined roles of this molecule in modulating inflammatory cytokine release in macrophages. Here, we review the functions of PI3Kγ in the immune system and discuss how our understanding of its potential as a therapeutic target has evolved.
Subject(s)
Class Ib Phosphatidylinositol 3-Kinase , Phosphatidylinositol 3-Kinases , Humans , Mice , Animals , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinase , Phosphoinositide-3 Kinase Inhibitors , Macrophages/metabolismABSTRACT
Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/ß-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.