Increased CTLA‐4⁺ T cells may contribute to impaired T helper type 1 immune responses in patients with chronic obstructive pulmonary disease

Abstract

Impaired T helper type 1 (Th1) function is implicated in the susceptibility of patients with chronic obstructive pulmonary disease (COPD) to respiratory infections, which are common causes of acute exacerbations of COPD (AECOPD). To understand the underlying mechanisms, we assessed regulatory T (Treg) cells and the expression of an inhibitory T-cell receptor, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Cryopreserved peripheral blood mononuclear cells (PBMC) from patients with AECOPD (n = 17), patients with stable COPD (sCOPD; n = 24) and age-matched healthy non-smoking controls (n = 26) were cultured for 24 hr with brefeldin-A or monensin to detect intracellular or surface CTLA-4 (respectively) by flow cytometry. T cells in PBMC from AECOPD (n = 9), sCOPD (n = 14) and controls (n = 12) were stimulated with anti-CD3 with and without anti-CTLA-4 blocking antibodies and cytokines were quantified by ELISA. Frequencies of circulating T cells expressing intracellular CTLA-4 were higher in sCOPD (P = 0·01), whereas patients with AECOPD had more T cells expressing surface CTLA-4 than healthy controls (P = 0·03). Increased frequencies of surface CTLA-4 CD4 T cells and CTLA-4 Treg cells paralleled increases in plasma soluble tumour necrosis factor receptor-1 levels (r = 0·32, P = 0·01 and r = 0·29, P = 0·02, respectively) in all subjects. Interferon-γ responses to anti-CD3 stimulation were inversely proportional to frequencies of CD4 T cells expressing intracellular CTLA-4 (r = -0·43, P = 0·01). Moreover, CTLA-4 blockade increased the induction of interferon-γ, tumour necrosis factor-α and interleukin-6 in PBMC stimulated with anti-CD3. Overall, chronic inflammation may expand sub-populations of T cells expressing CTLA-4 in COPD patients and therefore impair T-cell function. CTLA-4 blockade may restore Th1 function in patients with COPD and so aid the clearance of bacterial pathogens responsible for AECOPD.

Clinical significance of changes in serum inflammatory factors in patients with chronic obstructive pulmonary disease and pulmonary infection

“…High expression levels of inflammatory factors and diminished immune function in patients with COPD are associated with poor prognosis. 6 , 7 However, there have been few reports on the relationships between inflammatory indices, lung function, and immune function in these patients. Changes in inflammatory factors in patients with COPD and pulmonary infection play an essential role in diagnosis, treatment, and prognosis determination.…”

Peripheral Blood Mononuclear Cell Gene Expression in Chronic Obstructive Pulmonary Disease: miRNA and mRNA Regulation

“… 23–26 Impaired Th1 function is implicated in the susceptibility of patients with COPD to respiratory infections, which are common causes of acute exacerbation of COPD (AECOPD). 26 The present data revealed aberrant gene expression in iCOS- iCOSL signaling in the T helper cell pathway in COPD, suggesting a potential mechanism of impaired T cell response in COPD. This implied that patients with GOLD 3 and 4 COPD are more susceptible to infections and acute exacerbations, which may be due to impaired immune function.…”

Potential marker genes for chronic obstructive pulmonary disease revealed based on single-cell sequencing and Mendelian randomization analysis

“…The immune inflammation associated with COPD is at the heart of the disease, which is one of the reasons why current treatments have failed to stop the progression of the disease and the continued damage to lung tissue [ 29 ]. Previous studies have shown that the effector molecule functions of neutrophils and macrophages involved in chronic inflammation in COPD are suppressed [ 30 , 31 ]. In addition, it has been shown that neutrophils and lymphocytes can have a synergistic effect to enhance migration toward chemokine receptor 3 (CXCR3) and chemokine ligand 5 (CCL5), leading to immune infiltration of macrophages and T cells in the lungs of COPD patients [ 32 ].…”