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Activated pulmonary macrophages are insufficient for resistance against Pneumocystis carinii
R Hanano1, K Reifenberg, S H Kaufmann
1Department of Immunology, University of Ulm, Germany.
Abstract:
CD4+ T cells are pivotal for elimination of Pneumocystis carinii from infected lungs, and alveolar macrophages are considered the main effector cells clearing the infected host of P. carinii organisms. To investigate this issue, several mutant mouse strains were used in a previously established experimental setup which facilitates natural acquisition of disease through inhalation of airborne fungal organisms. Mutant mice deficient in major histocompatibility complex class II molecules (A beta(-/-)), T-cell receptor alphabeta 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 (IFN-gamma) receptor (IFN-gamma-R(-/-)) or tumor necrosis factor alpha (TNF-alpha) type I receptor (p55) (TNF-alpha-RI(-/-)) resisted disease acquisition. Analysis of pulmonary cytokine patterns and free radical expression revealed the presence of superoxide, nitric oxide, and interleukin-1 (IL-1) mRNA and elevated levels of IFN-gamma, TNF-alpha, and IL-12 in diseased TCR beta(-/-) and RAG-1(-/-) mice. Pulmonary macrophages of all diseased mouse mutants expressed scavenger and mannose receptors. Morbid A beta(-/-) mutants displayed significant NO levels and IL-1 mRNA only, whereas heterozygous controls did not exhibit any signs of 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 established 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 operative but did not suffice for parasite clearance in the absence of CD4+ TCR alphabeta cells. Therefore, additional pathways, possibly involving interactions of inflammatory cytokines with CD4+ T lymphocytes, must contribute to successful resistance against P. carinii.
Insights
CD4+ T cells are crucial for clearing Pneumocystis carinii infection. While activated macrophages fight the fungus, they are insufficient without CD4+ T cells, indicating other immune pathways are vital for resistance.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- CD4+ T cells are key to eliminating Pneumocystis carinii.
- Alveolar macrophages are thought to be the primary effector cells.
- Understanding the interplay of immune cells and cytokines in P. carinii infection is crucial.
Purpose of the Study:
- To investigate the roles of CD4+ T cells, macrophages, and cytokines in Pneumocystis carinii infection.
- To determine the necessity of specific immune components for resistance or susceptibility to P. carinii.
Main Methods:
- Utilized various mutant mouse strains (MHC class II, TCR, RAG-1, IFN-gamma-R, TNF-alpha-RI) to study P. carinii infection.
- Infected mice naturally via airborne fungal inhalation.
- Analyzed pulmonary cytokine profiles, free radical expression, and macrophage receptor expression.
Main Results:
- Mice lacking MHC class II, TCR alphabeta, or all T/B cells were susceptible to P. carinii.
- Mice lacking IFN-gamma or TNF-alpha receptors resisted infection.
- Activated phagocytes with cytokine/NO secretion were insufficient for parasite clearance without CD4+ T cells.
Conclusions:
- CD4+ T cells are essential for Pneumocystis carinii clearance.
- An activated phagocyte system alone cannot eliminate P. carinii.
- Immune resistance likely involves complex interactions between inflammatory cytokines and CD4+ T lymphocytes.