CCL11 increases the proportion of CD4(+)CD25(+)Foxp3(+) Treg cells and the production of IL-2 and TGF-β by CD4(+) T cells via the STAT5 signaling pathway

CD4(+) regulatory T (Treg) cells are associated with immune tolerance and antitumor immunosuppression. The aim of the present study was to investigate the role and molecular mechanism of C-C motif chemokine ligand 11 (CCL11) in the regulation of Treg cells from patients with breast cancer (BC) and healthy individuals in vitro, and from tumor-bearing mice in vivo. CD4(+) T cells isolated from patients with BC or healthy individuals were incubated with anti-CCL11 neutralizing antibodies or recombinant human CCL11 protein, in the presence or absence of a STAT5 inhibitor. The serum CCL11 level and proportion of Treg cells characterized as CD4(+)CD25(+)forkhead box P3(+) (Foxp3) among the CD4(+) T cells in patients with BC and healthy individuals were analyzed by ELISA and flow cytometry, respectively. CCL11, C-C motif chemokine receptor 3 (CCR3), Foxp3, phosphorylated-STAT5 and STAT5 expression levels were determined by western blotting. The serum CCL11 level and the proportion of CD4(+)CD25(+)Foxp3(+) Treg cells were significantly increased in patients with BC compared with healthy individuals. CCL11 blockade reduced the proportion of CD4(+)CD25(+)Foxp3(+) Treg cells, the expression of CCR3 and Foxp3, and the level of STAT5 activation in tumor-associated CD4(+) T cells, in a dose-dependent manner. CCL11 blockade also reduced the proportion of CD4(+)CD25(+)Foxp3(+) Treg cells and the serum levels of interleukin (IL)-2 and transforming growth factor (TGF)-β1 in tumor-bearing mice. The recombinant human CCL11 protein increased the proportion of CD4(+)CD25(+)Foxp3(+) Treg cells, the expression of CCR3 and Foxp3, and the release of IL-2 and TGF-β1 in non-tumor-associated CD4(+) T cells via the STAT5 signaling pathway. The results of the present study may aid in identifying therapeutics that could further modulate the immune system during BC.