DIRECT INTERACTIONS OF HUMAN NATURAL-KILLER-CELLS WITH CRYPTOCOCCUS-NEOFORMANS INHIBIT GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ANDTUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

Human natural killer (NK) cells and T lymphocytes can bind to and inhi bit the growth of the yeast-like organism Cryptococcus neoformans. Bin ding of target cells to NK or T cells also has the potential to modula te cytokine production by the effector cells. In this study, we assess ed the ability of C. neoformans to modulate NK cell production, or in some cases T-cell production, of granulocyte-macrophage colony-stimula ting factor (GM-CSF) or tumor necrosis factor alpha (TNF-alpha). We fo und that freshly isolated human NK cells from most individuals make GM -CSF and TNF-alpha constitutively when cultured in vitro. The addition of C. neoformans to T-cell fractions which do not make GM-CSF constit utively did not affect GM-CSF production, but the addition of C. neofo rmans to NK cell fractions significantly reduced the amounts of GM-CSF produced in most NK cell samples. The reduction in the amount of GM-C SF in C. neoformans-NK cell cocultures could not be attributed to loss of lymphocyte viability or to C. neoformans adsorbing or degrading th e cytokine and was dependent on direct contact between the NK cells an d cryptococcal cells. GM-CSF was not the only cytokine to be downregul ated. TNF-alpha production was also diminished when NK cells were incu bated with C. neoformans. The regulation of both cytokines was at the transcriptional level because GM-CSF and TNF-alpha mRNA levels were lo wer in NK cell samples incubated with C. neoformans than in NK cell sa mples incubated without C. neoformans. Diminished production of consti tutively produced cytokines resulting from the interaction of NK cells with cryptococcal cells has the potential to affect phagocytic cells in the immediate regional environment and to damp the immune response.