Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity

Abstract

Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (T cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

“…3, B -D). This is consistent with previous observations of increased pro-and pre-B cells in the endogenous repertoire of Pik3cd GOF mice, as well as of pre-B and immature B cells in the BM of patients with PIK3CD GOF mutations (Avery et al, 2018;Preite et al, 2018;Stark et al, 2018;Wray-Dutra et al, 2018). As with WT cells, we observed dramatically reduced proportions of mature self-reactive Pik3cd GOF SW HEL B cells ( Fig.…”

“…6 C and Fig. S5), consistent with the decreased ability of Pik3cd GOF B cells to undergo class switch recombination (Avery et al, 2018;Preite et al, 2018;Wray-Dutra et al, 2018) and the paucity of IgG autoreactive antibodies in PIK3CD GOF patients (Fig. S1).…”

“…Interestingly, ∼40% of PIK3CD GOF patients also develop clinically relevant autoimmune disease, including autoimmune cytopenias, glomerulonephritis, and autoimmune thyroiditis (Coulter et al, 2017;Lucas et al, 2014;Maccari et al, 2018). Several recent studies have explored the pathogenesis of the immunodeficiency in these patients (Avery et al, 2018;Bier et al, 2019;Cannons et al, 2018;Cura Daball et al, 2018;Edwards et al, 2019;Preite et al, 2018;Preite et al, 2019;Ruiz-García et al, 2018;Stark et al, 2018;Wentink et al, 2017;Wentink et al, 2018;Wray-Dutra et al, 2018). These studies have revealed defects in B cells and CD4 + T cells, thereby elucidating mechanisms for poor antibody responses and susceptibility to respiratory infections, and altered natural killer and CD8 + T cell function, which provide an explanation for the viral susceptibility and possibly malignancy.…”

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

“…Consistently, mice lacking p110δ (a subunit of PI3K highly expressed in lymphoid cells) in a T cell‐specific manner could not generate Tfh cells . Conversely, enhanced levels of PI3K signaling in T cells caused by PTEN deficiency in mice or activation mutations in the p110δ catalytic subunit of PI3K in humans and mice showed elevated Tfh responses. Using in vitro‐activated CD4 T cells, we and others have shown that acute co‐stimulation of ICOS‐enhanced IL‐21 mRNA expression.…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…Proper localization of Tfh cells in the light zone (LZ), a substructure of the GC, appears to be critical for their correct function. 36,37 In addition to expressing high levels of CXCR5 and low levels of CCR7 and PSGL1, this is achieved by downregulating S1PR1 and EBI2. 5…”