Dataset Information

NLRP3 Regulates IL-4 Expression in TOX⁺ CD4⁺ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

ABSTRACT: In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX⁺ CD4⁺ T cells that produce IL-4⁺ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4⁺ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX⁺ CD4⁺ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.

SUBMITTER: Huanosta-Murillo E

PROVIDER: S-EPMC8244903 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

Huanosta-Murillo Enrique E Alcántara-Hernández Marcela M Hernández-Rico Brenda B Victoria-Acosta Georgina G Miranda-Cruz Patricia P Domínguez-Gómez María Antonieta MA Jurado-Santacruz Fermín F Patiño-López Genaro G Pérez-Koldenkova Vadim V Palma-Guzmán Alam A Licona-Limón Paula P Fuentes-Pananá Ezequiel M EM Lemini-López Alicia A Bonifaz Laura C LC

Frontiers in immunology 20210616

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by whic ...[more]

PMID: 34220814

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Project description:BackgroundCutaneous T-cell lymphoma (CTCL) is highly heterogeneous, and its prognosis is closely related to the disease stage. The tumor microenvironment (TME) is an important component of tumor tissue, driving cancer cell growth, progression, and metastasis. However, the diagnostic value of TME in CTCL has not yet been studied in-depth. To date, no study has performed a comprehensive evaluation of the significance of the TME in CTCL.MethodsUsing xCell methods based on bulk RNA sequencing data, we inferred immune cell fraction in the TME in 126 patients and assessed the prognostic importance of immune cells. Consensus clustering was performed to determine the TME subtypes and characterize the transcriptome of each subtype. Based on the TME subtypes, we established the disease progression model using random forest algorithms and logistic regression. The efficacy of the model was examined using an additional 49-patient cohort. Finally, we validated our finding at the protein level using immunochemistry in a 16-patient cohort.ResultsPatients with advanced CTCL presented with a more active immunity overall than those with early stage. Random forest algorithms revealed that the immune cells CD4, macrophages, and dendritic cells (DCs) were the most effective prognosis predictors. Therefore, we constructed a risk model using logistic regression based on these immune cells. The TME score could be used to effectively predict disease conditions in three datasets with the AUC of 0.9414, 0.7912, and 0.7665, respectively. Immunochemistry at the protein level revealed that helper T cells and the macrophage markers CD4 and CD68 could successfully distinguish different CTCL stages in patients, whereas the DC marker langerin showed no change with disease progression.ConclusionWe found advanced-stage CTCL was associated with an active immune microenvironment, and the immune signatures CD4 and CD68 showed a relatively high accuracy in predicting CTCL disease progression.

Project description:BackgroundMycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL.MethodsSkin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence.ResultsMF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts.ConclusionSkin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.

Dataset Information

NLRP3 Regulates IL-4 Expression in TOX⁺ CD4⁺ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

Publications

NLRP3 Regulates IL-4 Expression in TOX<sup>+</sup> CD4<sup>+</sup> T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

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