TCR-dependent transformation of mature memory phenotype T cells in mice
Xi Wang, … , Harvey Cantor, Charles W.M. Roberts
Xi Wang, … , Harvey Cantor, Charles W.M. Roberts
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):3834-3845. https://doi.org/10.1172/JCI37210.
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Research Article Hematology

TCR-dependent transformation of mature memory phenotype T cells in mice

Abstract

A fundamental goal in cancer research is the identification of the cell types and signaling pathways capable of initiating and sustaining tumor growth, as this has the potential to reveal therapeutic targets. Stem and progenitor cells have been implicated in the genesis of select lymphoid malignancies. However, the identity of the cells in which mature lymphoid neoplasms are initiated remains unclear. Here, we investigate the origin of peripheral T cell lymphomas using mice in which Snf5, a chromatin remodelling–complex subunit with tumor suppressor activity, could be conditionally inactivated in developing T cells. In this model of mature peripheral T cell lymphomas, the cell of origin was a mature CD44hiCD122loCD8+ T cell that resembled a subset of memory cells that has capacity for self-renewal and robust expansion, features shared with stem cells. Further analysis showed that Snf5 loss led to activation of a Myc-driven signaling network and stem cell transcriptional program. Finally, lymphomagenesis and lymphoma proliferation depended upon TCR signaling, establishing what we believe to be a new paradigm for lymphoid malignancy growth. These findings suggest that the self-renewal and robust proliferative capacities of memory T cells are associated with vulnerability to oncogenic transformation. Our findings further suggest that agents that impinge upon TCR signaling may represent an effective therapeutic modality for this class of lethal human cancers.

Authors

Xi Wang, Miriam B.F. Werneck, Boris G. Wilson, Hye-Jung Kim, Michael J. Kluk, Christopher S. Thom, Jonathan W. Wischhusen, Julia A. Evans, Jonathan L. Jesneck, Phuong Nguyen, Courtney G. Sansam, Harvey Cantor, Charles W.M. Roberts

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Figure 1

Schematic of T cell development.

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Schematic of T cell development. CLP cells originate in the bone marrow ...
CLP cells originate in the bone marrow and migrate to the thymus. Cells at the CD4–CD8– DN stage are divided into 4 sequential subsets (DN1–DN4) according to expression of CD44 and CD25. Expression of the pre-TCR at DN3 leads to progression to DN4, followed by expression of CD4 and CD8 and progression to the CD4+CD8+ DP stage. Positive selection then leads to commitment toward the CD4 or the CD8 T cell lineage. Mature CD4 and CD8 single-positive cells then migrate to the periphery. The hCD2-Cre transgene is expressed at the CLP stage, leading to Snf5 deletion prior to arrival in the thymus. The Lck-Cre transgene is initially activated during early intrathymic development. The CD4-Cre transgene results in loss of Snf5 protein only in mature (CD4 and CD8) T cells in the periphery.