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* Department of Microbiology and Infectious Disease and
Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada;
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, China; and
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305
Granulysin is a cytolytic effector molecule used by lymphocytes to kill tumor and microbial cells. Regulation of granulysin production is complex. A significant delay (5 days) following stimulation of CD4+ T cells with IL-2 occurs before granulysin is produced. Unfortunately, the mechanisms responsible for this delay are unknown. We have recently demonstrated that granulysin-mediated killing of Cryptococcus neoformans by CD4+ T cells is defective during HIV infection. This is because CD4+ T cells from HIV-infected patients fail to produce granulysin in response to IL-2 activation. The present studies examined the mechanism of delayed production of granulysin and the mechanism of the defect in HIV patients. We demonstrate that IL-2 initially requires both STAT5 and PI3K activation to increase expression of IL-2Rβ, produce granulysin, and kill C. neoformans. The increased expression of IL-2Rβ precedes granulysin, and preventing the increased expression of IL-2Rβ using small interfering RNA knockdown abrogates granulysin expression. Moreover, following the increased expression of IL-2Rβ, blocking subsequent signaling by IL-2 using IL-2Rβ-specific blocking Abs abrogates expression of granulysin. Finally, CD4+ T cells from HIV-infected patients, who are defective in both STAT5 and PI3K signaling, fail to express IL-2Rβ and fail to produce granulysin. These results suggest that IL-2 signals via PI3K and STAT5 to increase expression of IL-2Rβ, which in turn is required for production of granulysin. These results provide a mechanism to explain the "late" production of granulysin during normal T cell responses, as well as for defective granulysin production by CD4+ T cells in HIV-infected patients.
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1 This work was supported by grants from Canadian Institute of Health Research (to C.H.M.), Canadian Foundation for AIDS Research (to C.H.M.), Jessie Bowden Lloyd Professorship in Immunology (to C.H.M.), and Canadian Institute of Health Research Training Program in Immunology (to C.F.Z.).
2 Address correspondence and reprint requests to Dr. Christopher H. Mody, Room 273, Heritage Medical Research Building, University of Calgary, Calgary, Alberta, Canada T2N 4N1. E-mail address: cmody{at}ucalgary.ca
3 Abbreviation used in this paper: siRNA, small interfering RNA.
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