THE ROLE OF THE CD28 B7 INTERACTION IN THE REGULATION OF NK CELL RESPONSES DURING INFECTION WITH TOXOPLASMA-GONDII/

We examined the role of the CD28/B7 interaction in regulation of NK ce ll activity. Cells transfected with B7 enhanced IL-12-induced producti on of IFN-gamma by IL-2-activated, CD28(+) NK cells, but not by restin g CD28(-) NK cells. The ability of B7 transfectants to enhance NK cell production of IFN-gamma was dependent on the intracellular adhesion m olecule-1/LFA-1 interaction and could be inhibited by TCF-beta, but no t IL-10. Since IL-12-induced production of IFN-gamma by NK cells is as sociated with resistance to certain infections, we examined whether th e CD28/B7 interaction regulated NK cell responses during infection. In fection of SCID mice with Toxoplasma gondii resulted in the appearance of a population of CD28(+) NK cells, NK cell production of IFN-gamma, and increased NK cell cytolytic activity. Administration of CTLA4-Ig to SCID mice infected with T. gondii inhibited these latter two effect s and resulted in a significant increase in parasite burden. The stimu lus for CD28 expression by NK cells in SCID mice infected with T. gond ii appeared to be independent of IL-2. However, mRNA for IL-15, a cyto kine with properties similar to those of IL-2, was detected in tissues of SCID mice infected with T. gondii. In vitro experiments demonstrat ed that IL-15 could stimulate resting NK cells to express functionally active CD28 as well as enhance the production of IFN-gamma by SCID sp lenocytes stimulated with T. gondii. Together our data demonstrate tha t the interaction of CD28(+) NK cells with B7 regulates NK cell produc tion of IFN-gamma associated with resistance to infection and that IL- 15 may be involved in these events.