Production of transmembrane and secreted forms of tumor necrosis factor (TNF)-α by HIV-1-specific CD4+ cytolytic T lymphocyte clones: Evidence for a TNF-α-independent cytolytic mechanism

A. Y. Liu, E. P. Miskovsky, P. E. Stanhope, R. F. Siliciano

Research output: Contribution to journalArticlepeer-review

Abstract

Candidate AIDS vaccines consisting of recombinant forms of the HIV-1 envelope glycoprotein induce, in seronegative human volunteers, an env- specific T cell response that includes CD4+, MHC class II-restricted CTL capable of lysing HIV-1-infected target cells. In this study, we have analyzed the production of the cytokines TNF-α and lymphotoxin (LT) by a set of env-specific CD4+ human CTL clones. TNF-α and LT are of interest because of their potential role in target cell destruction by CD4+ CTL. Our studies focused on the possibility that a cell surface form of TNF-α expressed by CTL after physiologic activation with target APC might participate in the cytolytic reactions mediated by these clones. We found that, upon interaction with target cells expressing env epitopes in the context of the appropriate MHC class II molecules, CD4+ CTL released TNF-α with kinetics that were rapid, compared with other cytokines, and that were generally similar to the kinetics of target cell destruction. LT secretion was not detected during the time course of the cytolytic reactions. A novel flow cytometric assay was used to show that physiologic activation of CD4+ CTL with target APC induced expression by the CTL of cell surface forms of TNF-α. Immunoprecipitations from activated, surface-iodinated CTL clones revealed two forms of surface TNF-α, a 26-kDa form, representing the transmembrane precursor of secreted TNF-α, as well as the 17-kDa secreted form bound to the cell surface. For a subset of CD4+ CTL, we found that treatment of CTL with cyclosporine A inhibited Ag-induced production of both transmembrane and secreted forms of TNF-α but had no effect on cytolysis. Thus, although transmembrane and secreted TNF-α produced by HIV-1-specific CD4+ CTL may have important effects in vivo, the rapid destruction of target APC by the set of CD4+ CTL clones described here occurs through a TNF-α-independent mechanism.

Original languageEnglish (US)
Pages (from-to)3789-3798
Number of pages10
JournalJournal of Immunology
Volume148
Issue number12
StatePublished - 1992

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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