IL-15 and DAP-10 mediated IL-22 production by Natural Killer cells in human Mycobacterium tuberculosis-infection. (134.7)

Abstract We studied the mechanisms of IL-22 production by NK cells in human Mycobacterium tuberculosis (M. tb) infection. CD3-CD56+ NK cells from 17 healthy donors produced IL-22 upon culturing with autologous monocytes and irradiated M. tb (417 ± 99 vs 52 ± 22 pg/ml, p < 0.001). In 14 healthy donors anti-IL-15 and anti-IL-23 reduced IL-22 production by NK cells from 494 ± 110 pg/ml to 193 ± 50 pg/ml (p = 0.01) and 256.1 ± 64.7 pg/ml (p = 0.03) respectively. In contrast, anti-IL-12 and anti-IL-18 had no effect. Recombinant IL-15 induced IL-23 receptor expression (18.7 ± 5.1% vs 6.7 ± 1.9%, p =0.03). Recombinant IL-15 induced IL-22 production by NK cells (4294 ± 1627 vs 43.50 ± 29 pg/ml, p=0.04), but recombinant IL-12 and 1L-18 had no effect. To identify signaling pathways involved in IL-15 mediated IL-22 production, we cultured NK cells from healthy donors with recombinant IL-15 for 48 hrs. In 5 healthy donors IL-15-stimulated NK cells expressed 12 times more DAP10 mRNA compared to control NK cells. In 8 healthy donors DAP10 siRNA inhibited IL-15-mediated IL-22 production by NK cells, compared to control siRNA-transfected NK cells (346 ± 121 vs 1248 ± 465 pg/ml, p =0.05). Studies are underway to determine the effect of IL-22 on intracellular survival of M. tuberculosis in macrophages. We conclude that IL-15 and DAP-10 are involved in IL-22 production by NK cells in human M. tb infection.