Generation And Immune Regulation Of CD4~+CD25~-Foxp3~+T Cells In Chronic Obstructive Pulmonary Disease

Part ? Generation and immune function of CD4~+CD25~-Foxp3~+T cells in chronic obstructive pulmonary diseaseThe imbalance of CD4~+Foxp3~+T cell subsets is reportedly involved in abnormal inflammatory immune responses in patients with chronic obstructive pulmonary disease(COPD).However,the possible role of CD4~+CD25~-Foxp3~+T cells in immune regulation in COPD remains to be investigated.In the current study,distribution and phenotypic characteristics of peripheral CD4~+CD25~-Foxp3~+T cells in COPD patients were determined by flow cytometry;the origin and immune function of CD4~+CD25~-Foxp3~+T cells were further explored in vitro.It was observed that circulating CD4~+CD25~+Foxp3~+T cells were significantly increased in patients with acute exacerbation of COPD(AECOPD);the frequency of CD4~+CD25~-Foxp3~+T cells was markedly increased in stable COPD patients(SCOPD).Phenotypic analysis revealed that CD4~+CD25~+Foxp3~+T cells resembled central memory or effector memory T cells.CD4~+CD25~+Foxp3~+T cells were induced when na(?)ve CD4~+T cells were activated through TCR stimulation independent of exogenous TGF?1;inversely,TGF?1 decreased CD25 expression and played a critical role in the generation of CD4~+CD25~-Foxp3~+T cells from CD4~+CD25~+Foxp3~+T cells.Compared with CD4~+CD25~+Foxp3~+T cells,CD4~+CD25~-Foxp3~+T cells lost the expression of Tregs-associated molecules following the reduction in CD25.Importantly,memory CD4~+CD25~-Foxp3~+T cells facilitated the proliferation of na(?)ve CD4~+T cells in cell-contact dependent manner.Taken together,we suggest that TGF?1 reduces CD25 expression and generates CD4~+CD25~-Foxp3~+T cells from CD4~+CD25~+Foxp3~+T cells in stable COPD patients following the resolution of the exacerbation.Part ? The interplay between CD4~+CD25~-Foxp3~+T cells and Th17 cells in chronic obstructive pulmonary diseaseTh17 cells,an important subset of effector CD4~+T cells,mediate neutrophil inflammation and are closely related to the pathogenesis of COPD.An imbalance of circulating CD4~+Foxp3~+T cells and Th17 cells results in immune dysfunction and the deterioration of pulmonary function in COPD.Therefore,it is increasingly urgent to elucidate the interplay between CD4~+CD25~-Foxp3~+T cells and Th17 cells in COPD patients.In this section,we will examine the distribution of peripheral Th17 cells in healthy non-smokers,smokers with normal lung function,SCOPD patients and patients with AECOPD,and further analyze their relationship with pro-inflammatory cytokines.In vitro,we will further explore the effect of CD4~+CD25~-Foxp3~+T cells on the differentiation of Th17 cells.Our results showed that the frequency of Th17 cells was significantly increased in patients with COPD.The concentration of IL-1?,IL-6 and IL-23 were also increased in COPD patients.Interestingly,under the condition of Th17 polarization,memory CD4~+CD25~-Foxp3~+T cells functionally promoted the precocious differentiation of naive CD4~+T cells into Th17 cells.In adition,a fraction of CD4~+CD25~-Foxp3~+T cells,exhibiting instability and plasticity,were transformed into Th17 cells.In summary,our results showed that CD4~+CD25~-Foxp3~+T cells functionally exert an auxiliary effect on Th17 cells generation and might perpetuate chronic inflammation in COPD.