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.