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

TL;DR

This study identifies a new mutation in the PIK3CD gene that causes immune dysfunction by increasing CD38 expression on B cells, leading to B cell senescence and immunodeficiency.

Contribution

The study reveals a novel PIK3CD mutation and its role in B cell dysfunction via FOXO1-regulated CD38 expression, offering new therapeutic insights.

Findings

The PIK3CD (R437C) mutation causes elevated CD38 expression on B cells, leading to senescence and mitochondrial dysfunction.

FOXO1, downstream of PI3K/AKT signaling, regulates CD38 by binding to its promoter, linking the pathway to B cell dysfunction.

mTORC2 is preferentially activated over mTORC1 in this mutation, contributing to immune dysregulation.

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.

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