ACTIVATED PULMONARY MACROPHAGES ARE INSUFFICIENT FOR RESISTANCE AGAINST PNEUMOCYSTIS-CARINII

CD4(+) T cells are pivotal for elimination of Pneumocystis carinii fro m infected lungs, and alveolar macrophages are considered the main eff ector cells clearing the infected host of P. carinii organisms. To inv estigate this issue, several mutant mouse strains were used in a previ ously established experimental setup which facilitates natural acquisi tion of disease through inhalation of airborne fungal organisms. Mutan t mice deficient in major histocompatibility complex class II molecule s (A beta(-/-)), T-cell receptor alpha beta cells (TCR beta(-/-)), or all mature T and B lymphocytes (RAG-1(-/-)) were naturally susceptible to P. carinii, whereas mouse mutants lacking the gamma interferon (IF N-gamma) receptor (IFN-gamma-R-/-) or tumor necrosis factor alpha (TNF -alpha) type I receptor (p55) (TNF-alpha-RI-/-) resisted disease acqui sition. Analysis of pulmonary cytokine patterns and free radical expre ssion revealed the presence of superoxide, nitric oxide, and interleuk in-1 (IL-1) mRNA and elevated levels of IFN-gamma, TNF-alpha, and IL-1 2 in diseased TCR beta(-/-) and RAG-1(-/-) mice. Pulmonary macrophages of all diseased mouse mutants expressed scavenger and mannose recepto rs. Morbid A beta(-/-) mutants displayed significant NO levels and IL- 1 mRNA only, whereas heterozygous controls did not exhibit any signs o f disease. Interestingly, neither IFN-gamma nor TNF-alpha appeared to be essential for resisting natural infection with P. carinii, nor were these cytokines sufficient for mediating resistance during establishe d disease in the absence of CD4(+) T lymphocytes. Taken together, the results indicated that an activated phagocyte system, as evidenced by cytokine and NO secretion, in diseased mutants was apparently operativ e but did not suffice for parasite clearance in the absence of CD4(+) TCR alpha beta cells. Therefore, additional pathways, possibly involvi ng interactions of inflammatory cytokines with CD4(+) T lymphocytes, m ust contribute to successful resistance against P. carinii.