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1.
J Exp Med ; 219(6)2022 06 06.
Article in English | MEDLINE | ID: mdl-35604411

ABSTRACT

Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation that these cell fates are mutually exclusive and that mature CD4+CD8+ double positive (DP) T cells are present in healthy individuals and augmented in the context of disease, yet their molecular features and pathophysiologic role are disputed. Here, we show DP T cells in murine and human tumors as a heterogenous population originating from SP T cells which re-express the opposite co-receptor and acquire features of the opposite cell type's phenotype and function following TCR stimulation. We identified distinct clonally expanded DP T cells in human melanoma and lung cancer by scRNA sequencing and demonstrated their tumor reactivity in cytotoxicity assays. Our findings indicate that antigen stimulation induces SP T cells to differentiate into DP T cell subsets gaining in polyfunctional characteristics.


Subject(s)
CD4-Positive T-Lymphocytes , Melanoma , Animals , CD4 Antigens/metabolism , CD8 Antigens/metabolism , CD8-Positive T-Lymphocytes , Cell Differentiation , Cell Lineage/genetics , Melanoma/metabolism , Mice , T-Lymphocyte Subsets
2.
Mol Cell Endocrinol ; 419: 185-97, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26525414

ABSTRACT

The thyroid hormone receptor α1 (TRα1) is a nuclear receptor for thyroid hormone that shuttles rapidly between the nucleus and cytoplasm. Our prior studies showed that nuclear import of TRα1 is directed by two nuclear localization signals, one in the N-terminal A/B domain and the other in the hinge domain. Here, we showed using in vitro nuclear import assays that TRα1 nuclear localization is temperature and energy-dependent and can be reconstituted by the addition of cytosol. In HeLa cells expressing green fluorescent protein (GFP)-tagged TRα1, knockdown of importin 7, importin ß1 and importin α1 by RNA interference, or treatment with an importin ß1-specific inhibitor, significantly reduced nuclear localization of TRα1, while knockdown of other importins had no effect. Coimmunoprecipitation assays confirmed that TRα1 interacts with importin 7, as well as importin ß1 and the adapter importin α1, suggesting that TRα1 trafficking into the nucleus is mediated by two distinct pathways.


Subject(s)
Cell Nucleus/metabolism , Karyopherins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Thyroid Hormone Receptors alpha/metabolism , alpha Karyopherins/metabolism , beta Karyopherins/metabolism , HeLa Cells , Humans , Protein Transport , Quinazolines/pharmacology , Signal Transduction/drug effects , Temperature
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