Absence of Both IL-7 and IL-15 Severely Impairs the Development of CD8+ T Cell Response against Toxoplasma gondii (original) (raw)
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Microbes and Infection, 2012
Long-term protection against Toxoplasma gondii is dependent on robust CD8 þ T cell immunity. In the absence of this response, the host is unable to maintain chronicity, which results in recrudescence of infection and possible death. Factors needed for the persistence of protective CD8 þ T cells against the parasite need to be evaluated. Previous studies from our laboratory have reported that synergism between g chain cytokines like IL-7 and IL-15 is critical for the generation of CD8 þ T cell response needed for protection during acute infection. In this study we report that the situation is different during the recall response where CD8 þ T cell response is almost entirely dependent on IL-15, with IL-7 at best playing a minor role. In the absence of IL-15, CD8 þ T cells fail to respond optimally to parasitic re-challenge and hosts are unable to control their replication, which leads to their death. Thus T. gondii infection may represent a unique situation where CD8 þ T cell response during secondary challenge is primarily dependent on IL-15 with other g chain cytokines having nominal effect. These findings provide important information regarding factors involved in the generation of protective immunity against T. gondii with strong implications in developing immunotherapeutic agents against the pathogen.
Proceedings of the National Academy of Sciences, 2006
IFN-␥-producing CD4 ؉ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-␥-producing CD4 ؉ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4 ؉ T cells from WT to IL-15 ؊/؊ mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Downregulated CD4 ؉ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4 ؉ T cells from IL-15 ؊/؊ mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4 ؉ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4 ؉ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4 ؉ T cell-mediated autoimmune diseases.
Journal of Experimental Medicine, 2002
Interferon (IFN)-␥ -producing CD8 ϩ T cells are important for the successful resolution of the obligate intracellular parasite Toxoplasma gondii by preventing the reactivation or controlling a repeat infection. Previous reports from our laboratory have shown that exogenous interleukin (IL)-15 treatment augments the CD8 ϩ T cell response against the parasite. However, the role of endogenous IL-15 in the proliferation of activated/memory CD8 ϩ T cells during toxoplasma or any other infection is unknown. In this study, we treated T. gondii immune mice with soluble IL-15 receptor ␣ (sIL-15R ␣ ) to block the host endogenous IL-15. The treatment markedly reduced the ability of the immune animals to control a lethal infection. CD8 ϩ T cell activities in the sIL-15R ␣ -administered mice were severely reduced as determined by IFN-␥ release and target cell lysis assays. The loss of CD8 ϩ T cell immunity due to sIL-15R ␣ treatment was further demonstrated by adoptive transfer experiments. Naive recipients transferred with CD44 hi activated/memory CD8 ϩ T cells and treated with sIL-15R ␣ failed to resist a lethal T. gondii infection. Moreover, sIL-15R ␣ treatment of the recipients blocked the ability of donor CD44 hi activated/memory CD8 ϩ T cells to replicate in response to T. gondii challenge. To our knowledge, this is the first demonstration of the important role of host IL-15 in the development of antigen-specific memory CD8 ϩ T cells against an intracellular infection.
Infection and Immunity, 2002
T-cell immunity is critical for survival of hosts infected with Toxoplasma gondii. Among the cells in the T-cell population, CD8 ؉ T cells are considered the major effector cells against this parasite. It is believed that CD4 ؉ T cells may be crucial for induction of the CD8 ؉ -T-cell response against T. gondii. In the present study, CD4 ؊/؊ mice were used to evaluate the role of conventional CD4 ؉ T cells in the immune response against T. gondii infection. CD4 ؊/؊ mice infected with T. gondii exhibited lower gamma interferon (IFN-␥) messages in the majority of their tissues. As a result, mortality due to a hyperinflammatory response was prevented in these animals. Interestingly, T. gondii infection induced a normal antigen-specific CD8 ؉ -T-cell immune response in CD4 ؊/؊ mice. No difference in generation of precursor cytotoxic T lymphocytes (pCTL) or in IFN-␥ production by the CD8 ؉ -T-cell populations from the knockout and wild-type animals was observed. However, the mutant mice were not able to sustain CD8 ؉ -T-cell immunity. At 180 days after infection, the CD8 ؉ -T-cell response in the knockout mice was depressed, as determined by pCTL and IFN-␥ assays. Loss of CD8 ؉ -T-cell immunity at this time was confirmed by adoptive transfer experiments. Purified CD8 ؉ T cells from CD4 ؊/؊ donors that had been immunized 180 days earlier failed to protect the recipient mice against a lethal infection. Our study demonstrated that although CD8 ؉ -T-cell immunity can be induced in the absence of conventional CD4 ؉ T cells, it cannot be maintained without such cells.
Infection and immunity, 1997
Interleukin-10 (IL-10) is a cytokine which can inhibit T-cell and natural killer (NK) cell functions associated with cell-mediated immunity to intracellular infections. The production of IL-10 by mice infected with Toxoplasma gondii has been implicated in the suppression of lymphocyte proliferation observed during acute toxoplasmosis, as well as susceptibility to infection with this parasite. We have used C57BL/6 mice which lack a functional IL-10 gene (IL-10(-/-) mice) to investigate the role of IL-10 in acute toxoplasmosis. Intraperitoneal infection of IL-10(-/-) mice with T. gondii resulted in 100% mortality by day 13, whereas wild-type C57BL/6 (WT) mice survived acute infection. IL-10(-/-) mice infected with T. gondii had significantly higher serum levels of IL-12 and gamma interferon (IFN-gamma) than WT mice. Early mortality of infected IL-10(-/-) mice was prevented by treatment with IL-10 and significantly delayed by neutralizing antibodies to IL-12 and IFN-gamma. Further stud...
Infection and Immunity, 1999
Toxoplasma gondii remains a serious cause of morbidity and mortality in individuals that are immunosuppressed, patients with AIDS in particular. The cellular immune response, especially by gamma interferon (IFN-␥)-producing CD8 ؉ T cells, is an essential component of protective immunity against the parasite. In the present study the role of CD8 ؉ T cells during the reactivation of Toxoplasma infection in an immunocompromised murine model was evaluated. Chronically infected mice were challenged with LP-BM5 virus, and the kinetics of CD8 ؉ T-cell function was studied. At 10 weeks after viral infection, mice showed obvious signs of systemic illness and began to die.