Tumor necrosis factor-α induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface

Kristian Hallermalm, Katzutake Seki, Chenhong Wei, Chiara Castelli, Licia Rivoltini, Rolf Kiessling, Jelena Levitskaya

Research output: Contribution to journalArticle

Abstract

It is demonstrated that similar to interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α) induces coordinated changes at different steps of the major histocompatibility complex (MHC) class I processing and presentation pathway in nonprofessional antigen-presenting cells (APCs). TNF-α up-regulates the expression of 3 catalytic immunoproteasome subunits-LMP2, LMP7, and MECL-1-the immunomodulatory proteasome activator PA28α, the TAP1/TAP2 heterodimer, and the total pool of MHC class I heavy chain. It was also found that in TNF-α-treated cells, MHC class I molecules reconstitute more rapidly and have an increased average half-life at the cell surface. Biochemical changes induced by TNF-α in the MHC class I pathway were translated into increased sensitivity of TNF-α-treated targets to lysis by CD8+ cytotoxic T cells, demonstrating improved presentation of at least certain endogenously processed MHC class I-restricted peptide epitopes. Significantly, it was demonstrated that the effects of TNF-α observed in this experimental system were not mediated through the induction of IFN-γ. It appears to be likely that TNF-α-mediated effects on MHC class I processing and presentation do not involve any intermediate messengers. Collectively, these data demonstrate the existence of yet another biologic activity exerted by TNF-α, namely its capacity to act as a coordinated multi-step modulator of the MHC class I pathway of antigen processing and presentation. These results suggest that TNF-α may be useful when a concerted up-regulation of the MHC class I presentation machinery is required but cannot be achieved by IFN-γ.

Original languageEnglish (US)
Pages (from-to)1108-1115
Number of pages8
JournalBlood
Volume98
Issue number4
DOIs
StatePublished - Aug 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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