Gr-1high polymorphonuclear leukocytes and NK cells act via IL-15 to clear intracellular Haemophilus influenzae in experimental murine peritonitis and pneumonia

Polymorphonuclear leukocytes (PMNs) can be divided into Gr-1(high) and Gr-1(low) subpopulations, but the differences in the functions of these cells in the host are unknown. This study investigated the roles of these two cell populations in the clearance of an intracellular pathogen (Haemophilus influenzae) causing murine peritonitis and pneumonia. Microarray analysis and quantitative real-time PCR analysis of proteose peptone-elicited peritoneal murine PMNs showed that IL-15 mRNA levels were significantly higher in Gr-1(high) PMNs than in Gr-1(low) PMNs. In addition, IL-15 was produced only by Gr-1-positive PMNs, especially Gr-1(high) PMNs. IL-15 was required for efficient clearance of experimental murine H. influenzae pneumonia, as 4 days postinfection lungs from IL-15 knockout mice contained 50- to 100-fold more bacteria than did wild-type mouse lungs. Gr-1 PMN-depleted C57BL/6 mice were more susceptible to H. influenzae pneumonia than were Gr-1 PMN replete C57BL/6 mice or C57BL/6 nude mice, demonstrating that Gr-1 PMNs are important in the clearance of intracellular bacteria. IL-15-activated NK cells killed H. influenzae in PMNs. Flow cytometry confirmed the expression of CD69 on the cell membrane of IL-15-activated NK cells. Our results show that Gr-1(high) PMNs produce more IL-15 than Gr-1(low) PMNs, and that IL-15-activated NK cells protect against early infection by H. influenzae.