The Role Of ICOS Signaling In The Progression Of COPD

Adaptive immune disbalance has been identified crucial to chronic obstructive pulmonary disease(COPD)progression,among which,T helper cells and regulatory T(Treg)cells are two important participators.Inducible co-stimulator,ICOS,has been reported to be expressed on both pro-inflammatory CD4~+T helper cells and anti-inflammatory CD4~+Tregs,whose overall role in different diseases should be evaluated in a context-dependent manner.In this study,we found that the expression of ICOS was elevated in peripheral CD4~+T cells and CD4~+Tregs from COPD patients,both of which had a positive correlation with the severity of lung function of SCOPD patients.After that,we further analyzed the detailed phenotypes of ICOS~+T cells and ICOS~+Tregs from SCOPD patients.Compared with ICOS~-Tregs,ICOS~+Tregs had higher expression levels of Helios,Ki-67 and two inhibitory receptors PD-1 and TIGIT.The mean fluorescence intensity of FOXP3 was also higher in ICOS~+Tregs.However,combined with the correlation of high expression level of ICOS with the deterioration of lung function and the recognition that ICOS is a T cell activation marker,we suggest that ICOS~+Tregs could be unstable and represent a pro-inflammatory Treg subset.The higher expression level of PD-1 and TIGIT could be a result of TCR stimulation.ICOS~+CD4~+T cells mostly exhibited a central memory or effector memory phenotype,which had higher expression levels of CD27,CD28,CD69,PD-1,and TIGIT but lower levels of CD57 and KLRG-1,two markers associated with immunosenescence,ensuring them a superior potential to respond strongly and quickly to pathogen invasion.Therefore,the upregulated ICOS signaling may exhibit a pro-inflammatory role in COPD pathogenesis.To test this hypothesis,we investigated the relationship between ICOS and chemokine receptors.We demonstrated that similar to ICOS expression pattern,increased frequencies of CXCR3~+CD4~+T cells and CXCR3~+CD4~+Tregs were shown in COPD patients and the expression level of CXCR3 was identified to be elevated in ICOS~+T cells compared with that in ICOS~-T cells.Furthermore,during the in vitro CD4~+na(?)ve T cells induction experiment,we found that anti-ICOS functional m Ab addition could induce the expression of several chemokine receptors,including CXCR3,CCR4,CCR10,and CXCR5.In fact,we have shown in another study that higher percentage of CXCR3~+CD4~+T cells existed in the bronchoalveolar lavage fluid than in the peripheral blood obtained from the same patient.Therefore,we speculate that the increased CXCR3~+CD4~+T cells in the peripheral blood of COPD patients could be partly due to the activation of ICOS signaling,and CXCR3 expression promotes the migration of CD4~+T cells to the lung.In one word,ICOS signaling could promote the development of COPD through promoting CXCR3 induction and CXCR3~+Th1 cell aggregation in the lung.