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In this study, we demonstrate that malignant mature CD4+ T lymphocytes derived from cutaneous T cell lymphomas (CTCL) variably display some aspects of the T regulatory phenotype. Whereas seven cell lines representing a spectrum of primary cutaneous T cell lymphoproliferative disorders expressed CD25 and TGF-β, the expression of FOXP3 and, to a lesser degree, IL-10 was restricted to two CTCL cell lines that are dependent on exogeneous IL-2. IL-2, IL-15, and IL-21, all of which signals through receptors containing the common γ chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells. However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3. The IL-2-triggered induction of IL-10 and FOXP3 expression occurred by signaling through STAT3 and STAT5, respectively. Immunohistochemical analysis of the CTCL tissues revealed that FOXP3-expressing cells were common among the CD7-negative enlarged atypical and small lymphocytes at the early skin patch and plaque stages. Their frequency was profoundly diminished at the tumor stage and in the CTCL lymph node lesions with or without large cell transformation. These results indicate that the T regulatory cell features are induced in CTCL T cells by common γ chain signaling cytokines such as IL-2 and do not represent a fully predetermined, constitutive phenotype independent of the local environmental stimuli to which these malignant mature CD4+ T cells become exposed.

The molecular mechanisms that induce and maintain expression of the alarming interleukin-33 (IL-33) in endothelial cells are unknown. Based on the observation that IL-33 is also a marker of endothelial cell quiescence, we hypothesized that the Notch signaling pathway might be involved in regulation of IL-33 expression. Here we show that activation of Notch1 by immobilized Notch ligands was sufficient to induce nuclear IL-33 expression in human umbilical vein endothelial cells (HUVECs). Furthermore, IL-33 expression in confluent HUVECs was inhibited by the γ-secretase inhibitor DAPT or by blocking antibodies to Dll4, Jagged1 or Notch1, as well as by knockdown of the transcription factor RBP-Jκ. In vivo, expression of Dll4 but not Jagged1 was generally observed in all segments of quiescent vessels in healthy organs in both human and rat tissue, and therefore well correlated with expression of IL-33. Moreover, subcutaneous injections of DAPT markedly reduced expression of vascular IL-33, compatible with a role for Notch signaling in driving vascular IL-33 expression in vivo. Taken together, our data demonstrate that the alarmin IL-33 is a target of Notch and serve to further establish Notch signaling in innate immune defense.