Senescent B cells regulate CD38 expression via FOXO1 in pneumonia resulting from PIK3CD (R437C) mutations

Abstract

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a primary immunodeficiency characterized by hyperactivated lymphocytes and recurrent infections. This study presents a 2.5-year-old patient with a novel PIK3CD gene mutation (c.1309C>T; p. R437C) derived from his mother. We explored the immunological consequences of this mutation in both the patient and his mother, revealing defects in T cell differentiation, B cell maturation, and mitochondrial function. Notably, we found that the elevated CD38 expression on B cells is a key factor driving B cell senescence, mitochondrial dysfunction, and increased transitional B cell proportion, contributing to the observed immunodeficiency, such as diminished serum antibodies. Further investigations of the PI3K/AKT/mTOR pathway highlight a preferential activation of mTORC2 over mTORC1. We also demonstrate that the transcription factor FOXO1, a downstream molecule of PI3K/AKT signaling, regulates CD38 expression by binding to the promotor of the CD38 gene, linking this pathway to B cell dysfunction. This novel mutation expands the spectrum of PIK3CD mutations associated with APDS and provides new insights into the molecular mechanisms underlying B-cell senescence and other immune dysregulation. Moreover, targeting the AKT-FOXO1 axis could offer therapeutic potential to reverse B-cell dysfunction and improve immune responses in patients with PIK3CD mutations.

Keywords

PIK3CD mutation / APDS / B cell / cellular senescence / CD38

References

[1] Fruman DA , Chiu H , Hopkins BD et al. The PI3K pathway in human disease. Cell 2017; 170: 605- 35.

[2] Backer JM . The regulation of class IA PI 3-kinases by inter-subunit interactions. Curr Top Microbiol Immunol 2010; 346: 87- 114.

[3] Houslay DM , Anderson KE , Chessa T et al. Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. Sci Signal 2016; 9: ra82.

[4] Lucas CL , Chandra A , Nejentsev S et al. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol 2016; 16: 702- 14.

[5] Noorolyai S , Shajari N , Baghbani E et al. The relation between PI3K/AKT signalling pathway and cancer. Gene 2019; 698: 120- 8.

[6] Jamee M , Moniri S , Zaki-Dizaji M et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol 2020; 59: 323- 33.

[7] Angulo I , Vadas O , Garçon F et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 2013; 342: 866- 71.

[8] Okkenhaug K . Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol 2013; 31: 675- 704.

[9] Wang W , Min Q , Lai N et al. Cellular mechanisms underlying B cell abnormalities in patients with gain-of-function mutations in the PIK3CD gene. Front Immunol 2022; 13: 890073.

[10] Preite S , Gomez-Rodriguez J , Cannons JL et al. T and B-cell signaling in activated PI3K Delta syndrome:from immunodeficiency to autoimmunity. Immunol Rev 2019; 291: 154- 73.

[11] Wentink MWJ , Mueller YM , Dalm V et al. Exhaustion of the CD8(+) T cell compartment in patients with mutations in phosphoinositide 3-kinase delta. Front Immunol 2018; 9: 446.

[12] Lucas CL , Kuehn HS , Zhao F et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol 2014; 15: 88- 97.

[13] Cannons JL , Villarino AV , Kapnick SM et al. PI3Kδ coordinates tran-scriptional, chromatin, and metabolic changes to promote effector CD8(+) T cells at the expense of Central memory. Cell Rep 2021; 37: 109804.

[14] Klion AD , Ackerman SJ , Bochner BS . Contributions of eosinophils to human health and disease. Annu Rev Pathol 2020; 15: 179- 209.

[15] Avery DT , Kane A , Nguyen T et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J Exp Med 2018; 215: 2073- 95.

[16] Fujimoto M , Poe JC , Inaoki M et al. CD19 regulates B lymphocyte responses to transmembrane signals. Semin Immunol 1998; 10: 267- 77.

[17] Zeng F , Zhang J , Jin X et al. Effect of CD38 on B-cell function and its role in the diagnosis and treatment of B-cell-related diseases. J Cell Physiol 2022; 237: 2796- 807.

[18] Oliver AM , Martin F , Kearney JF . Mouse CD38 is down-regulated on germinal center B cells and mature plasma cells. J Immunol 1997; 158: 1108- 15.

[19] Rodríguez-Alba JC , Moreno-García ME , Sandoval-Montes C et al. CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen. Blood 2008; 111: 3644- 52.

[20] Asano T , Okada S , Tsumura M et al. Enhanced AKT phosphorylation of circulating B cells in patients with activated PI3Kδ syndrome. Front Immunol 2018; 9: 568.

[21] Xing YQ , Li A , Yang Y et al. The regulation of FOXO1 and its role in disease progression. Life Sci 2018; 193: 124- 31.

[22] Liao S , Liang L , Yue C et al. CD38 is involved in cell energy metabolism via activating the PI3K/AKT/mTOR signaling pathway in cervical cancer cells. Int J Oncol 2020; 57: 338- 54.

[23] Schieber M , Chandel NS . ROS function in redox signaling and oxidative stress. Curr Biol 2014; 24: R453- 62.

[24] Liu T , Stephan T , Chen P et al. Multi-color live-cell STED nanoscopy of mitochondria with a gentle inner membrane stain. Proc Natl Acad Sci U S A 2022; 119: e2215799119.

[25] Frasca D , Diaz A , Romero M et al. B cell immunosenescence. Annu Rev Cell Dev Biol 2020; 36: 551- 74.

[26] Gorgoulis V , Adams PD , Alimonti A et al. Cellular senescence:defining a path forward. Cell 2019; 179: 813- 27.

[27] Bai Y , Guedes AGP , Krishnan R et al. CD38 plays an age-related role in cholinergic deregulation of airway smooth muscle contractility. J Allergy Clin Immunol 2022; 149: 1643- 54.e8.

[28] Grewal SIS . The molecular basis of heterochromatin assembly and epigenetic inheritance. Mol Cell 2023; 83: 1767- 85.

[29] Narita M , Nũnez S , Heard E et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113: 703- 16.

[30] Sacco K , Uzel G , Feldman J , et al.; Activated PI3K Delta Syndrome [M]//ADAM M P. GeneReviews(^®). Seattle (WA); University of Washington, Seattle Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved 1993

[31] Arnold IC , Munitz A . Spatial adaptation of eosinophils and their emerging roles in homeostasis, infection and disease. Nat Rev Immunol 2024; 24: 858- 77.

[32] Kang BN , Ha SG , Ge XN et al. The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice. Am J Physiol Lung Cell Mol Physiol 2012; 302: L1179- 91.

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The Author(s). Published by Oxford University Press on behalf of Higher Education Press.