Abstract
CD8+ T cells play an essential role in the protection against both acute as well as chronic Toxoplasma gondii infection. Although the role of IL-15 has been reported to be important for the development of long-term CD8+ T cell immunity against the pathogen, the simultaneous roles played by both IL-15 and related γ-chain family cytokine IL-7 in the generation of this response during acute phase of infection has not been described. We demonstrate that while lack of IL-7 or IL-15 alone has minimal impact on splenic CD8+ T cell maturation or effector function development during acute Toxoplasmosis, absence of both IL-7 and IL-15 only in the context of infection severely down-regulates the development of a potent CD8+ T cell response. This impairment is characterized by reduction in CD44 expression, IFN-γ production, proliferation and cytotoxicity. However, attenuated maturation and decreased effector functions in these mice are essentially downstream consequences of reduced number of antigen-specific CD8+ T cells. Interestingly, the absence of both cytokines did not impair initial CD8+ T cell generation but affected their survival and differentiation into memory phenotype IL-7Rαhi cells. Significantly lack of both cytokines severely affected expression of Bcl-2, an anti-apoptotic protein, but minimally affected proliferation. The overarching role played by these cytokines in eliciting a potent CD8+ T cell immunity against T. gondii infection is further evidenced by poor survival and high parasite burden in anti IL-7 treated IL-15−/− mice. These studies demonstrate that the two cytokines, IL-7 and IL-15, are exclusively important for the development of protective CD8+ T cell immune response against T. gondii. To the best of our knowledge this synergism between IL-7 and IL-15 in generating an optimal CD8+ T cell immunity against intracellular parasite or any other infectious disease model has not been previously reported.
Highlights
Development of effective CD8+ T cell response is critical for the control of various intracellular pathogens including, T. gondii, an obligate intracellular parasite [1,2]
To determine the role of IL-7 and IL-15 in the induction of primary CD8+ T cell response against T. gondii infection, anti IL-7 antibody was administered to WT and IL-152/2 mice infected with T. gondii
The results presented in the current studies demonstrate that both IL-7 and IL-15 play an important role in the induction of primary CD8+ T cell response against T. gondii infection
Summary
Development of effective CD8+ T cell response is critical for the control of various intracellular pathogens including, T. gondii, an obligate intracellular parasite [1,2]. Both CD4+ and CD8+ T cell response is induced during acute T. gondii infection, long-term protection against the parasite is primarily dependent on CD8+ T cell subset [3]. Immune CD8+ T cells from T. gondii infected host are important source of IFN-c, a cytokine which is critical for survival against both acute as well as chronic phases of infection [3]. Importance of CD8+ T cell immunity against T. gondii infection is well established, the cytokines precisely involved in generating this response have not been well demonstrated
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