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TGFβ determines morphology and key cellular processes of activated CD4+ T cells

ABSTRACT: During an immune response, cells are simultaneously exposed to multiple cytokine signals that collectively determine their phenotype. Transforming growth factor β (TGFβ) is a pleiotropic cytokine acting as a key regulator of T-cell differentiation with activating and suppressive effects on their immune function. Here we identify and analyze the cellular responses of CD4+ T cells to TGFβ across signaling contexts by analyzing the responses of T cells to multiple cytokine mixtures in the presence or absence of TGFβ. We found that TGFβ had a profound dominant effect independent of the presence of other cytokines, modulating the expression of more than 4,000 genes. In the presence of TGFβ, cells exhibit lower expression of translation-related and apoptosis-related genes, accompanied by increased survival of activated T cells. Notably, cells cultured in the presence of TGFβ were smaller in size while preserving their proliferative ability. Accordingly, we identified a dense network of transcription factors that were modulated by TGFβ, suggesting a core gene set connecting TGFβ signaling to the regulation of T-cell size. We found N-Myc to be at the center of this network, and we directly show that TGFβ regulates its gene expression level, protein level, and nuclear localization. Our work provides a system to study cell size control and demonstrate the profound effect of TGFβ in the modulation and regulation of T-cell properties, expanding its role beyond guiding their phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE264451 | GEO | 2025/04/21

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

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TGFβ determines morphology and key cellular processes of activated CD4+ T cells

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