Late expression of granulysin by microbicidal CD4+ T cells requires PI3K- and STAT5-dependent expression of IL-2Rβ that is defective in HIV-infected patients

Chun Fu Zheng, Gareth J. Jones, Meiqing Shi, Jeremy C D Wiseman, Kaleb J. Marr, Byron M. Berenger, Shaunna M. Huston, M. John Gill, Alan M. Krensky, Paul Kubes, Christopher H. Mody

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 granu-Iysin-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.

Original languageEnglish (US)
Pages (from-to)7221-7229
Number of pages9
JournalJournal of Immunology
Volume180
Issue number11
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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