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Transforming Growth Factor-beta signaling in ?? thymocytes promotes negative selection.

ABSTRACT: In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-?) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-? in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.

SUBMITTER: McCarron MJ

PROVIDER: S-EPMC6923358 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection.

McCarron Mark J MJ Irla Magali M Sergé Arnauld A Soudja Saidi M'Homa SM Marie Julien C JC

Nature communications 20191219 1

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired ...[more]

PMID: 31857584

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Project description:Transforming growth factor beta (TGF?) plays a major role in the regulation of tumor initiation, progression, and metastasis. It is depended on the type II TGF? receptor (T?RII) for signaling. Previously, we have shown that deletion of T?RII in mammary epithelial of MMTV-PyMT mice results in shortened tumor latency and increased lung metastases. However, active TGF? signaling increased the number of circulating tumor cells and metastases in MMTV-Neu mice. In the current study, we describe a newly discovered connection between attenuated TGF? signaling and human epidermal growth factor receptor 2 (HER2) signaling in mammary tumor progression.All studies were performed on MMTV-Neu mice with and without dominant-negative T?RII (DNIIR) in mammary epithelium. Mammary tumors were analyzed by flow cytometry, immunohistochemistry, and immunofluorescence staining. The levels of secreted proteins were measured by enzyme-linked immunosorbent assay. Whole-lung mount staining was used to quantitate lung metastasis. The Cancer Genome Atlas (TCGA) datasets were used to determine the relevance of our findings to human breast cancer.Attenuated TGF? signaling led to a delay tumor onset, but increased the number of metastases in MMTVNeu/DNIIR mice. The DNIIR tumors were characterized by increased vasculogenesis, vessel leakage, and increased expression of vascular endothelial growth factor (VEGF). During DNIIR tumor progression, both the levels of CXCL1/5 and the number of CD11b+Gr1+ cells and T cells decreased. Analysis of TCGA datasets demonstrated a significant negative correlation between TGFBR2 and VEGF genes expression. Higher VEGFA expression correlated with shorter distant metastasis-free survival only in HER2+ patients with no differences in HER2-, estrogen receptor +/- or progesterone receptor +/- breast cancer patients.Our studies provide insights into a novel mechanism by which epithelial TGF? signaling modulates the tumor microenvironment, and by which it is involved in lung metastasis in HER2+ breast cancer patients. The effects of pharmacological targeting of the TGF? pathway in vivo during tumor progression remain controversial. The targeting of TGF? signaling should be a viable option, but because VEGF has a protumorigenic effect on HER2+ tumors, the targeting of this protein could be considered when it is associated with attenuated TGF? signaling.

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Transforming Growth Factor-beta signaling in ?? thymocytes promotes negative selection.

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Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection.

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