The susceptibility to bacterial infections is increased in COPD. This promotes exacerbations. IL-2 triggers CD4+/Th1-cell proliferation, which is important for infection defense. Bacterial endotoxin (LPS) activates MyD88/IRAK and TRIF/IKK/TBK1 pathways via toll-like receptor-4 (TLR4) in Th1-cells. Hypothesis: systemic defects in TLR pathways in CD4+/Th1-cells cause an impairment of IL-2-dependent immune responses to bacterial infections in COPD. Peripheral blood CD4+ T-cells of never-smokers, smokers without COPD and smokers with COPD (each n=10) were ex vivo activated towards Th1 and stimulated with LPS. IL-2, MyD88 and TRIF expression and cell proliferation was analyzed by ELISA, qRT-PCR, BrdU- and trypan blue-staining comparative among the cohorts. IL-2 release from activated T-cells was increased in COPD vs. smokers and never-smokers. LPS reduced IL-2 expression and T-cell proliferation. These effects were increased in COPD vs. never-smokers and inversely correlated with FEV₁ [% pred.]. The MyD88/TRIF ratio was decreased in Th1-cells of COPD. The suppression of IL-2 by LPS was abolished by MyD88/IRAK blockade in never-smokers but by TRIF/IKK/TBK1 blockade in COPD. Moxifloxacin restored IL-2 expression and T-cell proliferation in the presence of LPS by blocking p38MAPK. The increased IL-2 release from Th1-cells in COPD might contribute to airway inflammation in disease exacerbations. A switch from MyD88/IRAK to TRIF/IKK/TBK1 signalling amplifies the suppression of IL-2-dependent proliferation of CD4+ T-cells by LPS in COPD. This molecular pathology is of systemic origin, might impair adaptive immune responses and could explain the increased susceptibility to bacterial infections in COPD. Targeting TLR4-downstream signalling, for example, with moxifloxacin, might reduce exacerbation rates.