Absence of both IL-7 and IL-15 severely impairs the development of CD8 T cell response against Toxoplasma gondii.
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 gamma-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-gamma 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-7Ralpha(hi) 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.
Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC., USA.
Rajarshi
R
Bhadra
Hongbing
H
Guan
Imtiaz A
IA
Khan
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000469:parasitology*; D002453:Cell Cycle / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000172:deficiency* / Q000378:metabolism; D015851:Interleukin-7 / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010271:Parasites / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D013194:Staining and Labeling; D014122:Toxoplasma / Q000187:drug effects / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology / Q000469:parasitology; D015854:Up-Regulation / Q000187:drug effects; D014611:Vaccination
D000906:Antibodies; D019409:Interleukin-15; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D007371:Interferon-gamma; D001973:Bromodeoxyuridine