Late Expression of Granulysin by Microbicidal Cd4+ T Cells Requires Pi3K- and Stat5-Dependent Expression of Il-2R That Is Defective in Hiv-Infected Patients

Zheng, C.F.; Jones, G.J.; Shi, M.; Wiseman, J.C.D.; Marr, K.J.; Berenger, B.M.; Huston, S.M.; Gill, M.J.; Krensky, A.M.; Kubes, P.; Mody, C.H.

The Journal of Immunology 180(11): 7221-7229


DOI: 10.4049/jimmunol.180.11.7221
Accession: 068490882

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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-2Rbeta, produce granulysin, and kill C. neoformans. The increased expression of IL-2Rbeta precedes granulysin, and preventing the increased expression of IL-2Rbeta using small interfering RNA knockdown abrogates granulysin expression. Moreover, following the increased expression of IL-2Rbeta, blocking subsequent signaling by IL-2 using IL-2Rbeta-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-2Rbeta and fail to produce granulysin. These results suggest that IL-2 signals via PI3K and STAT5 to increase expression of IL-2Rbeta, 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.