Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

Abstract

Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapable of suppressing autologous CD4+CD25- T-cell proliferation, whereas suppressive function was intact in the other six patients. Suppressive activity of Tregs inversely correlated with the peripheral blood tumor burden. T-plastin gene expression, used as a Sezary cell marker, confirmed that Sezary cells were heterogeneous for CD25 expression. Mixed lymphocyte reactions demonstrated that CD4+CD25- T cells from patients who lacked functional Tregs were susceptible to suppression by Tregs from healthy controls, and had not become suppressive themselves. Furthermore, we found reduced expression of Foxp3 in the CD4+CD25+ Tregs of these patients relative to the other six CTCL patients and controls. Our findings thus indicate a dysfunction of peripheral Tregs in certain CTCL patients, which correlates with tumor burden.

Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

“…23,24,27,42 Our results showed that the overall expression of FoxP3 was decreased in early stage MF patients and declined further with disease progression, which is consistent with previous reports. [18][19][20][21] We also observed an inverse correlation between HIF-1a and FoxP3 expression both in paraffin tissues and in CD4…”

“…22 In CTCL, the expression of FoxP3 and the function of regulatory T cells have been reported to be impaired, which could have important implications in the disease process. 18,20 The regulatory mechanisms of FoxP3 expression have not been completely elucidated; however, it has been reported that hypoxia-inducible factor 1 alpha (HIF-1a) can positively regulate FoxP3 expression at the transcriptional level by directly binding to the FoxP3 promoter 23 or downregulate FoxP3 expression at the post-translational level via proteasomal degradation. 24 HIF-1a is a ubiquitous transcription factor that can be stabilized in low oxygen conditions and regulates cell homeostasis.…”

FOXP3+ regulatory T cells: Current controversies and future perspectives

“…Further, we have recently demonstrated that high FOXP3 + Treg numbers predict improved survival of patients with follicular lymphoma, while a marked reduction is found on their transformation to a more aggressive diffuse large B cell lymphoma [36]. Decreased number and function of FOXP3 + Treg have also been described in the plasma cell-derived malignancy multiple myeloma [37] and in Sezary syndrome, the aggressive leukaemic variant of cutaneous T cell lymphoma [27,38]. Since Treg can suppress B as well as T cell function [39,40], the expansion of such tumours may be slowed by Treg.…”

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

“…We have previously shown that because of the marked heterogeneity of tumour cell populations, isolation of CD4 þ T-cells is the most appropriate method to enrich for tumour cells without loss of tumour cell sub-populations. 32,33 Lymphoprep (Axis-shield, Kimbolton, UK) gradient centrifugation was used either directly to isolate peripheral blood lymphocytes or following incubation with RosetteSep CD4 þ T-cell enrichment cocktail (Stem Cell Technologies, Grenoble, France) to isolate CD4 þ T-cells.…”