HEAT-SHOCK-PROTEIN-65 INDUCED BY GAMMA-DELTA T-CELLS PREVENTS APOPTOSIS OF MACROPHAGES AND CONTRIBUTES TO HOST-DEFENSE IN MICE INFECTED WITH TOXOPLASMA-GONDII

We previously reported that gamma delta T cells mediate the expression of endogenous heat shock protein 65 (HSP65) in macrophages of mice wi th acquired resistance against infection with Toxoplasma gondii. We sh ow here that HSP65 contributes to protective immunity by preventing ap optosis of infected macrophages. Macrophages of BALB/c mice, which rea dily acquired resistance to T. gondii infection with the low virulence Beverley strain, strongly expressed HSP65, and only a few of these ma crophages underwent apoptosis. On the other hand, the BALB/c mite were susceptible to the infection with the high virulence RH strain of T. gondii; their macrophages did not express HSP65 and did undergo apopto sis. Mice depleted of gamma delta T cells using a mAb specific for TCR -gamma delta became highly susceptible to infection even with the Beve rley strain. In these mice, HSP65 expression was markedly suppressed, and their infected macrophages died via apoptosis. Apoptosis was induc ed in cultured macrophages or macrophage cell lines after infection in vitro with the RH strain, whereas apoptosis was prevented when HSP65 was induced in these cells, before infection, by activation with IFN-g amma and TNF-alpha. However, apoptosis associated with infection by T. gondii RH strain was not prevented when HSP65 synthesis was inhibited by introducing an antisense oligonucleotide for this protein into the cells before activation with IFN-gamma plus TNF-alpha. Thus, HSP65 ap pears to contribute to immunity by preventing the apoptosis of infecte d macrophages, and the high virulence Toxoplasma appears to have mecha nisms that allow these organisms to evade the host defense system by i nterfering with HSP65 expression.