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Dichotomous response to transforming growth factor ? after T cell receptor activation by naive CD4+ T cells from DBA/1 mice: enhanced retinoic acid receptor-related orphan nuclear receptor ?t expression yet reduced FoxP3 expression.

ABSTRACT: To investigate the molecular mechanism for biased interleukin-17 (IL-17) production by DBA/1 CD4+ T cells upon T cell receptor (TCR) and transforming growth factor ? (TGF?) stimulation.Purified naive CD4+ T cells were stimulated with anti-CD3/CD28 under Th1, Th2, Th17, and induced T regulatory (iTreg) cell conditions. Cytokine production was assayed by intracellular staining and enzyme-linked immunosorbent assay. Expression of transcription factors was determined by reverse transcription-polymerase chain reaction, flow cytometry, and immunoblotting techniques.Naive CD4+ T cells from DBA/1 mice produced more IL-17 under Th17 cell polarizing conditions as compared with those from C57BL/6 or BALB/c mice. Further investigation revealed no difference among the strains in terms of CD4+ T cell survival, upstream TCR signaling, or CD69 expression or in the phosphorylation of STAT-3 and expression of suppressor of cytokine signaling 3 that positively or negatively regulate IL-17 cell production. However, DBA/1 CD4+ T cells expressed increased levels of retinoic acid-related orphan receptor ?t (ROR?t). Furthermore, under iTreg cell polarizing conditions, DBA/1 CD4+ T cells showed a strikingly reduced level of FoxP3 expression. When interferon-? and IL-4 were blocked, FoxP3 expression increased but remained lower in DBA/1 CD4+ T cells following exposure to TGF? as compared with C57BL/6 CD4+ T cells. Moreover, DBA/1 CD4+ T cells showed reduced phosphorylation of Smad2 and Smad3 under both Th17 and iTreg cell polarizing conditions.These results indicate that naive CD4+ T cells from DBA/1 mice have a dichotomous response to TGF?: enhanced ROR?t, yet reduced FoxP3, up-regulation. This observation may help to elucidate the branch point of TGF? signaling that leads to skewed Th17, but reduced iTreg, cell differentiation.

SUBMITTER: Morita Y

PROVIDER: S-EPMC3107673 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Dichotomous response to transforming growth factor β after T cell receptor activation by naive CD4+ T cells from DBA/1 mice: enhanced retinoic acid receptor-related orphan nuclear receptor γt expression yet reduced FoxP3 expression.

Morita Yoshiaki Y Ismail Doaa M DM Elkon Keith B KB Chu Cong-Qiu CQ

Arthritis and rheumatism 20110101 1

<h4>Objective</h4>To investigate the molecular mechanism for biased interleukin-17 (IL-17) production by DBA/1 CD4+ T cells upon T cell receptor (TCR) and transforming growth factor β (TGFβ) stimulation.<h4>Methods</h4>Purified naive CD4+ T cells were stimulated with anti-CD3/CD28 under Th1, Th2, Th17, and induced T regulatory (iTreg) cell conditions. Cytokine production was assayed by intracellular staining and enzyme-linked immunosorbent assay. Expression of transcription factors was determine ...[more]

PMID: 20862680

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Project description:NR4A orphan nuclear receptors are involved in multiple biological processes which are important in tumorigenesis such as cell proliferation, apoptosis, differentiation, and glucose utilization. The significance of NR4A family member NURR1 (NR4A2) in breast cancer etiology has not been elucidated. The purpose of this study was to ascertain the impact of NURR1 expression on breast transformation, tumor growth, and breast cancer patient survival.We determined the expression of NURR1 in normal breast versus breast carcinoma in tissue microarrays (immunohistochemistry), tissue lysates (immunoblot), and at the mRNA level (publically available breast microarrays). In addition NURR1 expression was compared among breast cancer patients in cohorts based on p53 expression, estrogen receptor ? expression, tumor grade, and lymph node metastases. Kaplan-Meier survival plots were used to determine the correlation between NURR1 expression and relapse free survival (RFS). Using shRNA-mediated silencing, we determined the effect of NURR1 expression on tumor growth in mouse xenografts.Results from breast cancer tissue arrays demonstrate a higher NURR1 expression in the normal breast epithelium compared to breast carcinoma cells (p???0.05). Among cases of breast cancer, NURR1 expression in the primary tumors was inversely correlated with lymph node metastases (p???0.05) and p53 expression (p???0.05). Clinical stage and histological grade were not associated with variation in NURR1 expression. In gene microarrays, 4 of 5 datasets showed stronger mean expression of NURR1 in normal breast as compared to transformed breast. Additionally, NURR1 expression was strongly correlated with increase relapse free survival (HR?=?0.7) in a cohort of all breast cancer patients, but showed no significant difference in survival when compared among patients whom have not been treated systemically (HR?=?0.91). Paradoxically, NURR1 silenced breast xenografts showed significantly decreased growth in comparison to control, underscoring a biphasic role for NURR1 in breast cancer progression.NURR1 function presents a dichotomy in breast cancer etiology, in which NURR1 expression is associated with normal breast epithelial differentiation and efficacy of systemic cancer therapy, but silencing of which attenuates tumor growth. This provides a strong rationale for the potential implementation of NURR1 as a pharmacologic target and biomarker for therapeutic efficacy in breast cancer.

Dataset Information

Dichotomous response to transforming growth factor ? after T cell receptor activation by naive CD4+ T cells from DBA/1 mice: enhanced retinoic acid receptor-related orphan nuclear receptor ?t expression yet reduced FoxP3 expression.

Publications

Dichotomous response to transforming growth factor β after T cell receptor activation by naive CD4+ T cells from DBA/1 mice: enhanced retinoic acid receptor-related orphan nuclear receptor γt expression yet reduced FoxP3 expression.

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