Human CD56bright and CD56dim Natural Killer Cell Subsets Respond Differentially to Direct Stimulation with Mycobacterium bovis Bacillus Calmette‐Guérin

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Abstract
Mycobacterium bovis bacillus Calmette‐Guérin (BCG) is capable of directly stimulating several effector functions of human natural killer (NK) cells in the absence of interleukin‐12 and professional antigen presenting cells. To assess the contribution of two main human NK‐cell subsets (CD56dim and CD56bright) to the overall in vitro NK‐cell response to BCG, peripheral blood mononuclear cells depleted of nylon wool‐adherent cells or purified NK cells were stimulated with live BCG. By combining intranuclear bromodeoxyuridine (BrdU) staining and analysis of CD56 marker intensity, statistically higher percentages of BrdU+ cells were found among the CD56bright subset than the CD56dim subset after 6 days of stimulation with BCG. Similarly, evaluation of intracellular interferon‐γ (IFN‐γ) revealed that CD56bright cells were those mainly involved in IFN‐γ production in response to BCG. In contrast, the CD56dim subset contained higher levels of perforin and granzyme A, two key molecules for exocytosis‐mediated cytotoxicity, than the CD56bright subset. Although 16–20‐h stimulation with BCG did not substantially alter the expression of cytotoxic molecules by the two subsets, a decrease in perforin content was observed in the CD56dim, but not in the CD56bright subset, following 4‐h incubation with the NK‐sensitive target K562 cell line. This decrease in perforin content correlated with the induction by BCG‐stimulated NK cells, of early markers of apoptosis on target cells to a greater extent than unstimulated cells suggesting a major role for the CD56dim subset in cytotoxic activity in response to BCG. Taken together, these results demonstrate that CD56bright and CD56dim human NK‐cell subsets exert different functional activities in response to a live bacterial pathogen.

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