γc-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes

Abstract

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.

Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

“…By its feature of being constitutively expressed and activated, NPM/ ALK secures a persistent, steady expression of the CD274 protein by the ALKϩTCL cells. Considering our previous findings that NPM/ALK also induces expression of IL-10 and TGF-␤ (17), although not FoxP3, as we have clarified recently (22), these combined observations indicate that inhibition of immune response against ALKϩTCL cells is an important component of the NPM/ALK-mediated oncogenicity. It is also very interesting that NPM/ALK induces expression of these immunosuppressive proteins through STAT3.…”

“…NPM/ALK-expressing SUDHL-1, JB6, SUP-M2, Karpas 299, and L-82 cell lines were derived from ALKϩTCL patients (10,(15)(16)(17)(18). IL-2-dependent T cell line Sez-4 and IL-2-independent MyLa3675 were derived from a CTCL patient (21,22). Jurkat was developed from lymphoblastic T-cell lymphoma.…”

PLCG1 mutations in cutaneous T-cell lymphomas

“…Gene expression profiling studies have shown that increased signaling from the TCR can be considered a driving force of CTCL and that neoplastic T cells can show a degree of phenotypic plasticity, as characterized by the expression of a variety of lineage markers. [5][6][7][8][9] However, whether this is the result of signaling from the tumor stroma or the consequence of specific genetic alterations in the pathways involved in TCR signaling is still a matter of active research. [10][11][12] Early stages of CTCL are treated with combinations of UV and immunotherapy, with mono-or polychemotherapy being reserved for cases that do not respond to previous treatment.…”

Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS

“…5,6,19 Although it is not easy to fit ALK ϩ TCL into a specific functional CD4 ϩ T-cell subset considering the sometime overlapping features of the subsets and malignant, aberrant phenotype of the ALK ϩ TCL cells, it can be argued that the lymphoma cells resemble type 1 subcategory of Treg cells because of the production of large amounts of IL-10 and lack of expression of FoxP3. 12,21 Of note, ALK ϩ TCL also express an immunosuppressive cell-surface protein PD-L1 10 ; but in contrast to IL-10 and FoxP3 expression, PD-L1 has not so far been associated with any given category of normal Treg cells.…”

“…9,10 IL-2-dependent T-cell lines Sez-4 and SeAx and IL-2-independent Myla2059 and MyLa3675 were derived from CTCL, and PB-1, 2A, and 2B were derived from a patient with a primary skin CD30 ϩ lymphoproliferative disorder. 11,12 Jurkat cell line was developed from lymphoblastic T-cell lymphoma. The Epstein-Barr virus (EBV)-negative cell lines, Ly18 and Val, were derived from diffuse large B-cell lymphoma and Ramos from Burkitt lymphoma.…”