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,
Departments of
* Immunology and
Oncology, University of Washington, Seattle, WA 98195; and
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
CD8+ T cells respond to IL-2 produced both endogenously and by CD4+ Th during an antiviral response. However, IL-2R signals can potentially promote CD8+ T cell death as well as proliferation, making it unclear whether IL-2R signals provide a predominantly positive or negative effect upon CD8+ T cell responses to viral infection. To more precisely define the direct role of IL-2R signaling on CD8+ T cells during the response to a virus, we examined the effect of delivering augmented IL-2R signals selectively to CD8+ T cells responding to lymphocytic choriomeningitis virus infection. Although naive CD8+ T cells are competent to produce IL-2, CD8+ T cells lose this capacity upon differentiation into effector CD8+ T cells. However, effector CD8+ T cells do retain the capacity to produce GM-CSF upon Ag stimulation. Thus, to deliver enhanced autocrine IL-2R signals to CD8+ T cells, we established a transgenic mouse strain expressing a chimeric GM-CSF/IL-2R (GMIL2R). As GM-CSF production is Ag dependent, the GMIL2R delivers an augmented IL-2R signal exclusively to CD8+ T cells responding to Ag. Following lymphocytic choriomeningitis virus infection, GMIL2R transgenic mice exhibited an increase in both the peak CD8+ T cell response achieved and the size of the resulting memory pool established. Upon secondary viral challenge, the GMIL2R also enhanced the proliferative response of memory CD8+ T cells. Thus, our findings indicate that IL-2 delivery to responding CD8+ T cells is a limiting factor in both the acute and memory antiviral responses.
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