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This study investigated the effect of a high and low dose of caffeine on antigen-stimulated natural killer (NK) cell (CD3 ⁻ CD56 ⁺ ) activation after prolonged, strenuous cycling, as assessed by the early-activation molecule CD69. In a randomized crossover design, 12 healthy male endurance-trained cyclists cycled for 90 min at 70% VO _2peak 60 min after ingesting either 0 (PLA), 2 (2CAF), or 6 (6CAF) mg/kg body mass of caffeine. Whole blood was stimulated with Pediacel (5 in 1) vaccine. A high dose of caffeine (6CAF) increased the number of CD3 ⁻ CD56 ⁺ cells in the circulation immediately postexercise compared with PLA ( p < .05). For both 2CAF and 6CAF, the geometric mean fluorescence intensity (GMFI) of CD69 ⁺ expression on unstimulated CD3 ⁻ CD56 ⁺ cells was significantly …