When kept under strict specific-pathogen-free conditions, H-21-Abeta (Abeta(-/-),T-cell receptor beta (TCRbeta(-/-)), and recombinase-activating gene 1 (RAG-1(-/-) gene disruption mutant mice, deficient in conventional CD4+ T cells, TCRalphabeta cells, and all peripheral T and B lymphocytes, respectively, consistently developed lethal Pneumocystis carinii pneumonia through natural infection. The most severe symptoms appeared in RAG-1(-/-) mutants. In contrast, TCRdelta(-/-) and beta2-microglobulin(-/-)(beta2m-/-) mutants, deficient in TCRgammadelta cells and conventional CD8alphabeta+ TCRalphabeta cells, respectively, were fully resistant to infection. Our data indicate not only the insufficiency but also the dispensability of CD8 alphabeta+TCRalphabeta cells and of TCRgammadelta lymphocytes in resistance to P. carinii infection. Under disease conditions, large numbers of unusual single-positive CD4+ and CD8alphabeta+ as well as double-negative TCRgammadelta subpopulations of cells accumulated in lungs of TCRbeta(-/-) mutants. This accumulation was consistently accompanied by a drastic increase in the pulmonary B-cell population. In contrast, CD8alphabeta+ TCR alpha beta cells, but no B cells, appeared in lungs of parasitized Abeta (-/-) mutants. Since lung damage and parasite numbers were less prominent in morbid TCRbeta(-/-) and Abeta(-/-) mutants than in diseased RAG-1(-/-) mice, the remaining lymphocytes accumulating in lungs of the former two mutants seem to perform residual resistance functions.