Heat shock protein 65 induced by gammadelta T cells prevents apoptosis of macrophages and contributes to host defense in mice infected with Toxoplasma gondii.

Abstract

We previously reported that gammadelta T cells mediate the expression of endogenous heat shock protein 65 (HSP65) in macrophages of mice with acquired resistance against infection with Toxoplasma gondii. We show here that HSP65 contributes to protective immunity by preventing apoptosis of infected macrophages. Macrophages of BALB/c mice, which readily acquired resistance to T. gondii infection with the low virulence Beverley strain, strongly expressed HSP65, and only a few of these macrophages underwent apoptosis. On the other hand, the BALB/c mice were susceptible to the infection with the high virulence RH strain of T. gondii; their macrophages did not express HSP65 and did undergo apoptosis. Mice depleted of gammadelta T cells using a mAb specific for TCR-gammadelta became highly susceptible to infection even with the Beverley strain. In these mice, HSP65 expression was markedly suppressed, and their infected macrophages died via apoptosis. Apoptosis was induced 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-gamma 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 appears to contribute to immunity by preventing the apoptosis of infected macrophages, and the high virulence Toxoplasma appears to have mechanisms that allow these organisms to evade the host defense system by interfering with HSP65 expression.

Generation of Nitric Oxide by the Inducible Nitric Oxide Synthase Protects γδ T Cells fromMycobacterium tuberculosis-Induced Apoptosis

“…HSP that have been involved in ␥␦ T cell activation (44) and contribute to resistance to apoptosis of macrophages infected by Toxoplasma gondii are over-expressed in infected APC (45). Of interest, HSP expression has also been implicated in resistance to NO-mediated cytolysis (46).…”

Overview of Apoptosis, Autophagy, and Inflammatory Processes in Toxoplasma gondii Infected Cells

“…Hence, HSP65 appears to contributeto immune function by preventing apoptosis of infected macrophages and decreasing parasite survival and virulence. Under in vivo conditions, the Beverly strain, unlike the RH strain of T. gondii , induces the expression of HSP65 in the host gd-T cell [ 117 ].…”

Mycobacterial Heat Shock Proteins in Sarcoidosis and Tuberculosis

“…Others [ 51 , 65 , 67 ] have shown that the virulence of the strain-infecting phagocytes determines not only the production of cytokines, but also the level of HSP and the subsequent process of apoptosis. A high virulence of intracellular bacteria induces the apoptosis of infected monocytes/macrophages, while low virulence inhibits apoptosis and induces the development of an inflammatory process [ 51 , 66 , 67 , 68 ]. The high level of HSP produced by a cell infected with a low-pathogenic bacterium inhibits its apoptosis, probably as a result of accelerated maturation of Bcl-2 proteins [ 68 , 69 ].…”

“…A high virulence of intracellular bacteria induces the apoptosis of infected monocytes/macrophages, while low virulence inhibits apoptosis and induces the development of an inflammatory process [ 51 , 66 , 67 , 68 ]. The high level of HSP produced by a cell infected with a low-pathogenic bacterium inhibits its apoptosis, probably as a result of accelerated maturation of Bcl-2 proteins [ 68 , 69 ]. Previously published data [ 51 , 64 , 66 , 68 , 69 , 70 , 71 , 72 ] suggest an anti-apoptotic effect of mycobacterial HSP70 and HSP65 on mononuclear phagocytes by protecting the integrity of the mitochondrion and/or by combining heat shock proteins with an apoptotic protease-activating factor or the N-terminal fragment of c-Jun, BAG-1 or Bcl-2.…”

“…The high level of HSP produced by a cell infected with a low-pathogenic bacterium inhibits its apoptosis, probably as a result of accelerated maturation of Bcl-2 proteins [ 68 , 69 ]. Previously published data [ 51 , 64 , 66 , 68 , 69 , 70 , 71 , 72 ] suggest an anti-apoptotic effect of mycobacterial HSP70 and HSP65 on mononuclear phagocytes by protecting the integrity of the mitochondrion and/or by combining heat shock proteins with an apoptotic protease-activating factor or the N-terminal fragment of c-Jun, BAG-1 or Bcl-2. In vitro studies have shown that elevated levels of HSP70 reduce the monocyte apoptosis induced by TNF-α or NO and inhibit cytochrome c/d ATP-mediated activation of caspases [ 32 ], while Mtb-HSP70 can also induce the release of anti-apoptotic IL-10 [ 58 , 59 , 62 , 63 , 64 , 65 ].…”