Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin

Abstract

CD8 ؉ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8 ؉ T cells or deficient in perforin due to knockout of the ␤2-microglobulin (␤2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the ␤2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8 ؉ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.

The relative contribution of antibody production and CD8+ T cell function to immune control of Trypanosoma cruzi

“…Perforin/granzyme mediated cytolysis involves the release of granules containing perforin, which polymerizes to form pores in the target cell membrane, and granzymes which may enter through these pores and induce apoptosis of the target cell (Berke, 1995, Kagi et al 1996b). The generation of knockout mice lacking perforin or granzyme B has allowed investigators to explore the role of this pathway in CD8 þ T cell response in a number of systems (Heusel et al 1994, Kagi et al 1994a, b, Guidotti and Chisari, 1996, Denkers et al 1997, Laochumroonvorapong et al 1997, Renggli et al 1997, Tang et al 1997. In the present work we show that in T. cruzi infection, perforin/ granzyme-mediated cytolysis plays a rather minor role in the protective capacity of CD8 þ T cells.…”

Immune CD8+T Cells Prevent Reactivation ofToxoplasma gondiiInfection in the Immunocompromised Host

“…Evidence of disseminated infection similar to the control animals treated with naive CD8 ϩ T cells was revealed upon histopathological examination of the tissues. The intracellular multiplication of T. gondii and necrosis of tissues was superimposed on the lymphoid infiltrates, a finding typical of LP-BM5 MuLV infection (38). Infection with LP-BM5 MuLV alone produces an appearance in the spleen similar to that seen in dual-infected mice, without the evidence of increased phagocytosis.…”

Chronic fatigue syndrome is associated with diminished intracellular perforin

“…Two areas of research provided important insight in the role of perforin in normal and pathological conditions. The perforin knockout mouse, a model of perforin deficiency, demonstrated the role of perforin as a cytotoxic effector molecule through decreased cytotoxicity against virus infected and allogeneic targets [23] and reduced clearance of intracellular pathogens and tumours [24,25]. These mice had increased numbers of activated CD8 cells [26] and altered cytokine production with elevated expression of interleukin (IL)‐1, interferon (IFN)‐γ and TNF‐α[27–29].…”