# PI3Kdelta-driven expansion of regulatory B cells impairs protective immune responses to Trypanosoma congolense parasite infection

## TL;DR

A mutation in the PI3KCD gene causes regulatory B cells to expand, weakening the immune response to a parasite infection.

## Contribution

The study reveals how a PI3KCD mutation in B cells leads to impaired immune control during Trypanosoma congolense infection.

## Key findings

- Mice with the PI3KCDE1021K mutation show increased regulatory B cells and poor control of T. congolense infection.
- The mutation alters cytokine balance and impairs myeloid cell activation during early infection.
- Regulatory B cells express inhibitory molecules that likely suppress protective immune responses.

## Abstract

Phosphatidylinositol 3-kinase delta (PI3KCD) is a critical signaling enzyme for B cell development, activation, function and immune regulation. Gain-of-function mutations in PI3KCD result in the congenital immunodeficiency known as Activated PI3KCD Syndrome (APDS). APDS patients are prone to repeated infections and other serious clinical manifestations. Here, we determine how B cell-intrinsic expression of the APDS-associated PI3KCDE1021K mutation impacts immune responses to the protozoan parasite Trypanosoma congolense. PI3KCDE1021K/B mice exhibit a significant expansion of IL10-expressing B cells within the spleen and peritoneal cavity, which was associated with impaired control of T. congolense infection. Despite the generation of robust germinal center, plasma cell and antibody responses, PI3KCDE1021K/B mice show elevation in the first wave of parasitemia and increased mortality. We further characterize the phenotype of the expanded IL10-producing B cell population in PI3KCDE1021K/B mice, which show hallmarks of innate-like regulatory B cells (Breg) and expression of multiple inhibitory molecules. This Breg expansion is associated with reduced IFNγ/IL10 ratio, reduced TNFα production and impaired activation of myeloid cells, likely compromising the innate response to infection. These findings highlight the profound impact of dysregulated PI3KCD activity on regulatory B cells that can functionally impair innate immune responses controlling a systemic parasite protozoan disease.

B cells and antibodies play a critical role in the immune response to Trypanosome parasites. Molecular signaling networks within B cells can control the type of response generated during infection. Here, we studied how a genetic variant in the signaling enzyme PI3KCD, previously linked to human immune deficiencies, impacts B cell responses to Trypanosome infection. We find that mice expressing the PI3KCDE1021K mutation in their B cells show impaired control of Trypanosome infection, and alterations in several aspects of the immune response. Specifically, we noted these mice poorly control parasite growth within the first week of infection, a timeframe where specific antibody responses have not yet been generated. We noted an altered balance between pro-inflammatory and anti-inflammatory cytokine mediators produced within the first week of infection. This was associated with high numbers of regulatory B cells expressing multiple molecules capable of inhibiting other cells of the immune system. We further found that these mice show functional alterations in other critical immune cell types, such as macrophages and T cells. These findings highlight the impact of dysregulated PI3KCD activity on regulatory B cells that can impair immune responses controlling a systemic parasite protozoan disease.