Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence.

Wasem, Christoph; Arnold, Diana; Saurer, Leslie; Corazza, Nadia; Jakob, Sabine; Herren, Simon; Vallan, Claudio; Mueller, Christoph; Brunner, Thomas (2003). Sensitizing antigen-specific CD8+ T cells for accelerated suicide causes immune incompetence. Journal of clinical investigation, 111(8), pp. 1191-1199. American Society for Clinical Investigation 10.1172/JCI16344

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Death receptor-mediated activation-induced apoptosis of antigen-specific T cells is a major mechanism of peripheral tolerance induction and immune homeostasis. Failure to undergo activation-induced cell death (AICD) is an important underlying cause of many autoimmune diseases. Thus, enhancing the T cell's own suicide mechanism may provide an efficient therapy for the treatment of autoimmune diseases. Bisindolylmaleimide VIII (Bis VIII), a PKC inhibitor, can sensitize T cells for death receptor-induced apoptosis and thus can inhibit the development of T cell-mediated autoimmune disease in vivo. In this study, we have analyzed the functional consequences of accelerated suicide for a protective CD8+ T cell-mediated immune response. Our data indicate that CD8+ T cells are sensitized by Bis VIII to AICD, both in vitro and in vivo. The sensitizing effect of Bis VIII appears to be mediated by specific downmodulation of the antiapoptotic molecule cellular FLICE-like inhibitory protein (cFLIP(L)). Importantly, Bis VIII administration during an acute lymphocytic choriomeningitis virus (LCMV) infection causes the depletion of virus-specific CD8+ T cells and subsequently impaired cytotoxicity and virus clearance. We conclude that resistance to death receptor-induced apoptosis is crucial for the efficient induction of a protective immune response, and that Bis VIII-based immunotherapies have to be applied under well-controlled conditions to avoid the induction of immune incompetence and the inability to respond to pathogen infection.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Müller, Christoph and Brunner, Thomas

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Christoph Müller

Date Deposited:

23 Sep 2022 15:50

Last Modified:

23 Sep 2022 15:59

Publisher DOI:

10.1172/JCI16344

PubMed ID:

12697738

BORIS DOI:

10.48350/173169

URI:

https://boris.unibe.ch/id/eprint/173169

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