Selective suicide of cross-presenting CD8(+) dendritic cells by cytochrome c injection shows functional heterogeneity within this subset

Lin, ML; Zhan, Y; Projetto, AI; Prato, S; Wu, L; Heath, WR; Villadangos, JA; Lew, AM

Author(s): Lin, ML; Zhan, Y; Projetto, AI; Prato, S; Wu, L; Heath, WR; Villadangos, JA; Lew, AM;
Details: Publication Year 2008-02-26,Volume 105,Issue #8,Page 3029-3034
Journal Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Publication Type: Journal Article
Abstract: Cross-presentation as a fundamental pathway of activating CD8(+) T cells has been well established. So far the application of this concept in vivo is limited, and the mechanisms that specialize CD8(+) dendritic cells (DCs) for this task are not fully understood. Here we take advantage of the specific cytosolic export feature of cross-presenting DCs together with the property of cytosolic cytochrome c (cyt c) in initiating Apaf-1-dependent apoptosis selectively in cross-presenting DCs. A single i.v. injection of cyt c in B6 mice produced a 2- to 3-fold reduction in splenic CD8(+) DCs but not in Apaf-1-deficient mice. Functional studies both in vivo and in vitro showed that cyt c profoundly abrogated OVA-specific CD8(+) T cell proliferation through its apoptosis-inclucing effect on cross-presenting DCs. More importantly, in vivo injection of cyt c abolished the induction of cytotoxic T lymphocytes to exogenous antigen and reduced subsequent immunity to tumor challenge. in addition, only a proportion of CD8(+) DCs that express abundant IL-12 and Toll-like receptor 3 were efficient cross-presenters. Our data, support the hypothesis that cross-presentation in vivo requires cytosolic diversion of endocytosed proteins, conferring cross-presentation specialization to a proportion of CD8(+) DCs. We propose that DCs incapable of such transfer, even within the CD8(+) DC subset, are unable to cross-present. Our model opens an avenue to specifically target cross-presenting DCs in vivo for manipulating cytotoxic T lymphocyte responses toward infections, tumors, and transplants.
Publisher: NATL ACAD SCIENCES
Keywords: CLASS-I PRESENTATION; T-CELLS; TRANSGENIC MICE; ANTIGEN; VIVO; CROSSPRESENTATION; ACTIVATION; GENERATION; APOPTOSOME; EXPRESSION
Publisher's Version: https://doi.org/10.1073/pnas.0712394105
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2008-02-26 12:00:00