Background: In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4+ T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties. Methods: Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n = 25) and healthy volunteers (n = 25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT2 Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test. Results: In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4+ and TH17 IL-17A+ cells, and a higher percentage of IFN-γ/IL-10 and IL-4/IL-10 double-releasing CD4+ T cells. In addition, we also observed the up-regulation of innate immunity genes and the down-regulation of adaptive immunity ones. Conclusions: Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.

Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients

Di Rorà, Andrea Ghelli Luserna;Lucchesi, Alessandro;Bonafè, Massimiliano;Martinelli, Giovanni
2018

Abstract

Background: In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4+ T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties. Methods: Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n = 25) and healthy volunteers (n = 25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT2 Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test. Results: In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4+ and TH17 IL-17A+ cells, and a higher percentage of IFN-γ/IL-10 and IL-4/IL-10 double-releasing CD4+ T cells. In addition, we also observed the up-regulation of innate immunity genes and the down-regulation of adaptive immunity ones. Conclusions: Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.
De Matteis, Serena*; Molinari, Chiara; Abbati, Giulia; Rossi, Tania; Napolitano, Roberta; Ghetti, Martina; Di Rorà, Andrea Ghelli Luserna; Musuraca, Gerardo; Lucchesi, Alessandro; Rigolin, Gian Matteo; Cuneo, Antonio; Calistri, Daniele; Fattori, Pier Paolo; Bonafè, Massimiliano; Martinelli, Giovanni
File in questo prodotto:
File Dimensione Formato  
12967_2018_Article_1545.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione 2.37 MB
Formato Adobe PDF
2.37 MB Adobe PDF Visualizza/Apri
12967_2018_1545_MOESM1_ESM.docx

accesso aperto

Descrizione: Fig. S1. Representative box plots relative to IL-23 levels (pg/ml) in plasma from HV (n = 10) and CLL (n = 10). Results are expressed as median and interquartile range. P value shown is obtained from the comparison between the indicated groups by exact non-parametric Mann–Withney U test (*P < 0.05).(
Tipo: File Supplementare
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 62.27 kB
Formato Microsoft Word XML
62.27 kB Microsoft Word XML Visualizza/Apri
12967_2018_1545_MOESM2_ESM.doc

accesso aperto

Descrizione: Table S1. List of genes involved in innate and adaptive immunity.(12
Tipo: File Supplementare
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 122 kB
Formato Microsoft Word
122 kB Microsoft Word Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/668001
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 17
social impact