title: Systemic LPS Translocation Activates Cross-Presenting Dendritic Cells but Is Dispensable for the Breakdown of CD8+ T Cell Peripheral Tolerance in Irradiated Mice.
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.
authors.affiliation: Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France; Université Montpellier, UFR de Médecine, Montpellier, F-34000, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Espinosa-Carrasco
authors.affiliation: Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France; Université Montpellier, UFR de Médecine, Montpellier, F-34000, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Villard
authors.affiliation: CMRS/Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, United States of America.
authors.forename: Cecile
authors.initials: C
authors.lastname: Le Saout
authors.affiliation: Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France; Université Montpellier, UFR de Médecine, Montpellier, F-34000, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Louis-Plence
authors.affiliation: Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France; Université Montpellier, UFR de Médecine, Montpellier, F-34000, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Vicente
authors.affiliation: Inserm U1183, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34295, France; Université Montpellier, UFR de Médecine, Montpellier, F-34000, France.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernandez
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D045142:Cross-Priming; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D061166:Peripheral Tolerance / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides