Systemic LPS Translocation Activates Cross-Presenting Dendritic Cells but Is Dispensable for the Breakdown of CD8+ T Cell Peripheral Tolerance in Irradiated Mice

PLoS One. 2015 Jun 15;10(6):e0130041. doi: 10.1371/journal.pone.0130041. eCollection 2015.

Abstract

Lymphodepletion is currently used to enhance the efficacy of cytotoxic T lymphocyte adoptive transfer immunotherapy against cancer. This beneficial effect of conditioning regimens is due, at least in part, to promoting the breakdown of peripheral CD8+ T cell tolerance. Lymphodepletion by total body irradiation induces systemic translocation of commensal bacteria LPS from the gastrointestinal tract. Since LPS is a potent activator of the innate immune system, including antigen presenting dendritic cells, we hypothesized that LPS translocation could be required for the breakdown of peripheral tolerance observed in irradiated mice. To address this issue, we have treated irradiated mice with antibiotics in order to prevent LPS translocation and utilized them in T cell adoptive transfer experiments. Surprisingly, we found that despite of completely blocking LPS translocation into the bloodstream, antibiotic treatment did not prevent the breakdown of peripheral tolerance. Although irradiation induced the activation of cross-presenting CD8+ dendritic cells in the lymphoid tissue, LPS could not solely account for this effect. Activation of dendritic cells by mechanisms other than LPS translocation is sufficient to promote the differentiation of potentially autoreactive CD8+ T cells into effectors in irradiated mice. Our data indicate that LPS translocation is dispensable for the breakdown of CD8+ T cell tolerance in irradiated mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cross-Priming
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology*
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Peripheral Tolerance / immunology*
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism

Substances

  • Anti-Bacterial Agents
  • Lipopolysaccharides

Grant support

This work was supported by grants from the European Community SUDOE-FEDER (Contract # IMMUNONET SOE1/P1/E014) and La Ligue Contre le Cancer Hérault to JH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.