Could the Crosstalk Between Myeloid-Derived-Suppressor Cells and Regulatory T Cells Have a Role in Beta-Thalassemia?

Abstract

Background: Secondary iron overload, alloimmunization, and increased risk of infection are common complications in patients with transfusion-dependent thalassemia (TDT). Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) play an essential role in preventing excessive immune response. This research aimed to study the interaction between Tregs and MDSCs in TDT patients and to evaluate the association of these cell types with disease severity.

Methods: This case-control study included 26 patients with TDT and 23 healthy, age- and sex-matched controls. All patients were investigated for complete blood count (CBC), serum ferritin, and flow cytometric analysis of peripheral blood to detect Tregs, MDSCs, and MDSC subsets.

Results: A significant increase was observed in the frequencies of Tregs and MDSCs, particularly monocytic MDSCs (MO-MDSCs), in TDT patients compared with controls. The frequencies of these cells showed a direct association with ferritin level and total leukocyte count and an inverse association with hemoglobin level. Furthermore, a positive correlation was observed between Tregs and each of the total MDSCs and MO-MDSCs.

Conclusions: Levels of Tregs and MDSCs increased in TDT and may probably have a role in suppressing the active immune systems of TDT patients.

Keywords: Children; Myeloid-derived-suppressor cells; Regulatory T cells; β-thalassemia.

Figure 1

Representative plots showing flow cytometric detection of regulatory T cells in transfusion-dependent thalassemia (TDT) patients. (a) The lymphocyte population was defined on a forward scatter (FSC) and side scatter (SSC) histogram (R1). (b) The expression of CD4 on the lymphocytes population was detected, then CD4⁺ cells were gated (R2) for further analysis of CD25. (c) Three gates were drawn to define CD4⁺CD25^- cells (R3), CD4⁺CD25^+low cells (R4), and CD4⁺CD25^+high cells (R5). (d) The percentage of CD4⁺CD25^+highFoxp3⁺ cells (regulatory T cells) was then assessed. Foxp3: forkhead box protein 3; FITC: fluorescein isothiocyanate; PE: phycoerythrin; Per-CP: peridinium-chlorophyll-protein.

Figure 2

Representative plots showing flow cytometric detection of myeloid-derived suppressor cells (MDSCs) in transfusion-dependent thalassemia (TDT) patients. (a) HLA-DR negative cells (R1) were selected from HLA-DR and side scatter histogram. (b) HLA-DR negative cells were assessed for their expression of CD33 and CD11b to detect total MDSCs (R2) (HLA-DR^-CD33⁺CD11b⁺). (c, d) Total MDSCs were assessed for their expression of CD15 and CD14 to detect polymorphonuclear MDSCs (PMN-MDSCs) (HLA-DR^-CD33⁺CD11b⁺CD15⁺) and monocytic MDSCs (MO-MDSCs) (HLA-DR^-CD33⁺CD11b⁺CD14⁺). HLA-DR: human leukocyte antigen - DR isotype; Foxp3: forkhead box protein 3; FITC: fluorescein isothiocyanate; PE: phycoerythrin; Per-CP: peridinium-chlorophyll-protein; SSC: side scatter.

Figure 3

Correlations of CD4⁺CD25^highFoxP3⁺ Tregs with serum ferritin level (a), total leukocyte count (TLC) (b), and hemoglobin (HB) level (c). Foxp3: forkhead box protein 3; Tregs: regulatory T cells.

Figure 4

Correlations of total myeloid-derived suppressor cells (MDSCs) with serum ferritin level (a), total leukocyte count (TLC) (b), platelet (PLT) count (c), and hemoglobin (HB) level (d).

Figure 5

Correlations of monocytic-myeloid-derived suppressor cells (MO-MDSCs) with serum ferritin level (a), total leukocyte count (TLC) (b), and hemoglobin (HB) level (c).

Figure 6

Correlations of CD4⁺CD25^highFoxP3⁺ Tregs with monocytic-myeloid-derived suppressor cells (MO-MDSCs) (a) and total myeloid-derived suppressor cells (MDSCs) (b). Foxp3: forkhead box protein 3; Tregs: regulatory T cells.