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The B cell receptor-mTOR signaling axis restricts the accumulation of lung tissue-resident memory B cells following influenza infection

ABSTRACT: Lung tissue-resident memory B (BRM) cells are important in establishing protective immunity against respiratory pathogens. However, the pathways regulating the accumulation of lung BRM cells are poorly understood. Here we show that the transcription factors NFATC1 (nuclear factor of activated T cells 1) and EGR2 (early growth response 2) repress lung BRM cell accumulation following influenza infection, whereas IKZF1 (IKAROS family zinc finger 1) enhances it. IKZF1 restrains B cell receptor (BCR) and mTOR (mechanistic target of rapamycin) signaling and is highly expressed in lung BRM cells during their development. Lung BRM cells display reduced expression of genes associated with BCR and mTOR signaling pathways. Overexpression of a degradation-resistant form of SYK downstream of the BCR restricted lung BRM cell accumulation. Conversely, inhibition of mTOR using rapamycin reduced NFATC1 and EGR2 expression and promoted lung BRM cell accumulation. These findings establish how the BCR–mTOR signaling axis regulates mucosal B cell responses following influenza infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE314077 | GEO | 2026/03/20

REPOSITORIES: GEO

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Project description:Deletions within the human IKZF1 gene, which encodes Ikaros, a zinc finger transcription factor critical for lymphopoiesis, appear to be the most prominent recurring lesion in human BCR-ABL1+ (Ph+) B-ALL. Furthermore, IKZF1 mutations correlate with poor prognosis of progenitor B-ALL, further strengthening the notion that IKZF1 is a critical tumor suppressor gene in human B-lineage malignancies. To better understand the relationship between Ikzf1 mutations, BCR-ABL, and B-lineage leukemia, we examined the effect of two newly generated Ikzf1 germline mutation on BCR-ABL-induced proliferation and leukemogenesis in vitro and in vivo. We recently showed that deletion of either the exon encoding the first or the fourth DNA-binding zinc finger of Ikaros (IkZnF1-/- and IkZnF4-/-) led to distinct defects in lymphoid development and tumor suppression with de-regulation of distinct subsets of genes, providing a powerful tool for elucidation of Ikaros target genes and mechanism of function. Importantly, IkZnF4-/- had lost Ikaros tumor suppression function, while not abolishing B-cell development. Retroviral expression of BCR-ABL1 p185 in bone marrow cells from the two Ikzf1 mutant strains demonstrated that loss of ZnF4 resulted in expansion of progenitor B cells, with enhanced proliferation in vitro and a less mature cell surface B-cell phenotype in comparison to transduced wild-type bone marrow. Furthermore, in an in vivo model of BCR-ABL+ B-ALL, leukemias generated in the IkZnF4-/- background were more aggressive than those observed in a wild-type background, with cell phenotype corresponding to the in vitro cell cultures. Genome wide high throughput expression analysis (RNA-Seq) revealed a distinct subset of deregulated genes in the IkZnF4-/- BCR-ABL+ in vitro cell cultures, and molecular analysis demonstrated that this in vitro system is amendable for functional studies. These results establish a mouse model for studying the role of Ikzf1 mutations in B-ALL, and for understanding how BCR-ABL collaborates with Ikzf1 mutations to generate aggressive B-ALL.

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The B cell receptor-mTOR signaling axis restricts the accumulation of lung tissue-resident memory B cells following influenza infection

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