BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation that persists after the cessation of smoking. T cells have a major role in driving inflammation in patients with COPD and are activated by specific antigens to produce mediators, such as cytokines. The antigens that activate lung T cells have not been clearly defined. Nontypeable Haemophilus influenzae (NTHi) is the dominant bacterium isolated from the lungs of patients with COPD. OBJECTIVE: We sought to measure the response of lung tissue T cells to stimulation with NTHi. METHODS: We obtained lung tissue from 69 subjects having lobectomies for lung cancer. Of the group, 39 subjects had COPD, and 30 without COPD were classified as control subjects. The lung tissue was dispersed into single-cell suspensions and stimulated with live NTHi. Cells were labeled with antibodies for 5 important inflammatory mediators in patients with COPD and analyzed by using flow cytometry. RESULTS: NTHi produced strong activation of both TH cells and cytotoxic T cells in the COPD cohort. The COPD cohort had significantly higher levels of cells producing TNF-α, IL-13, and IL-17 in both T-cell subsets. When control subjects were divided into those with and without a significant smoking history and compared with patients with COPD, there was a progressive increase in the numbers of T cells producing cytokines from nonsmoking control subjects to smoking control subjects to patients with COPD. CONCLUSION: NTHi activates lung T cells in patients with COPD. This proinflammatory profibrotic response might be a key cause of inflammation in patients with COPD and has implications for treatment.