The delayed ontogenesis of Ia-positive macrophages: Implications for host defense and self-tolerance in the neonate

We have recently compared a number of macrophage functions in newborn and adult mice. In the adult, the most efficient resistance against Listeria infection requires a number of macrophage-T lymphocyte interactions which ultimately result in activated macrophages which eliminate the bacteria. A subpopulation of adult macrophages are distinguished by the presence of cell-surface, immune-response-gene-associated (Ia) antigens. These macrophages ingest and then 'present' antigen to and thus activate T lymphocytes. Extensive in vitro experiments have shown that T lymphocyte activation requires both antigen and Ia-bearing macrophages. Ia-negative macrophages are not involved in this process. The T lymphocyte thus stimulated secretes lymphokines which then activate macrophages to acquire bactericidal and tumoricidal activity. In contrast to the adult mouse, essentially no Ia-bearing antigen presenting macrophages can be found in the neonatal spleen and peritoneal cavity. Neonatal and adult macrophages were similar in all other examined aspects - phagocytic activity, cytocidal function after lymphokine stimulation, and interleukin-1 secretion after exposure to endotoxin. The absence of Ia-bearing macrophages in neonates would be expected to contribute to their increased susceptibility to Listeria. The absence of Ia-bearing macrophages in the neonate is not the result of any intrinsic defects in these cells, as they can be made to express Ia in vitro. Nor is the deficit in Ia-bearing macrophages due to the hyporeactivity of neonatal helper T lymphocytes as adult athymic mice have significant numbers of Ia-bearing macrophages. Neonatal splenocytes or their conditioned media inhibit macrophage Ia expression when transferred into adult mice. The suppressor cell appears to be an immature phagocyte. Its inhibitory activity was abolished by indomethacin, suggesting it exerted its inhibitory influence via arachidonic acid metabolites. In fact, PGE₂ inhibits macrophage Ia expression in vitro.