Functional transitions in macrophages during in vivo infection with Mycobacterium bovis bacillus Calmette-Guerin

Macrophage activation during the immune response to intracellular bacteria is critical for resolution of the infection. We have investigated the pathw ay of macrophage activation during murine Mycobacterium bovis bacillus Calm ette-Guerin (BCG) infection. Three distinct phenotypes of macrophages were identified and compared: resident peritoneal macrophages, day 2 postinfecti on macrophages, and 12-day postinfection macrophages. Compared with residen t peritoneal macrophages, day 2 BCG macrophages expressed intermediate leve ls of the cell surface receptors Mac1 and F4/80 and low levels of MHC class II molecules. These cells were highly phagocytic and produced large amount s of mRNA encoding the chemokine IP-10. In addition, day 2 BCG macrophages did not generate reactive nitrogen intermediates, though they were primed t o do so, and did not have increased levels of TNF-alpha mRNA. Blockade of m onocyte influx into the peritoneal cavity using Abs to platelet endothelial cell adhesion molecule I had no effect on the appearance of day 2 BCG macr ophages, suggesting this cell can differentiate from resident peritoneal ma crophages. In contrast to day 2 BCG macrophages, day 12 BCG macrophages wer e poorly phagocytic, but produced high levels of reactive nitrogen intermed iates, IP-10 and TNF-alpha mRNA, and class II MHC molecules. We propose tha t day 2 BCG macrophages are specialized for phagocytic uptake of pathogens from the extracellular space, whereas day 12 BCG macrophages are specialize d for killing of the internalized pathogens. This functional transition dur ing activation is reminiscent of that seen during maturation/activation of the related dendritic cell lineage induced by bacterial or inflammatory sti muli.