2. Academic Validation
  3. PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells

PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells

  • Nat Immunol. 2024 Jul 3. doi: 10.1038/s41590-024-01890-1.
Stephen M Lanahan 1,  Lucas Yang 1,  Kate M Jones 1,  Zhihong Qi 1,  Emylette Cruz Cabrera 2,  Lauren Y Cominsky 3,  Anjali Ramaswamy 1,  Anis Barmada 1,  Gisela Gabernet 4,  Dinesh Babu Uthaya Kumar 1,  Lan Xu 1,  Peiying Shan 1,  Matthias P Wymann 5,  Steven H Kleinstein 1 4 6,  V Koneti Rao 7,  Peter Mustillo 8,  Neil Romberg 2 9,  Roshini S Abraham 10,  Carrie L Lucas 11
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 2 Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 3 Immunology Graduate Group, Perelman School of Medicine, Philadelphia, PA, USA.
  • 4 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
  • 5 Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 6 Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
  • 7 Primary Immunodeficiency Clinic, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA.
  • 8 Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
  • 9 Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, USA.
  • 10 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
  • 11 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Carrie.Lucas@yale.edu.
PMID: 38961274 DOI: 10.1038/s41590-024-01890-1
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.

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