title: Irradiation and IL-15 promote loss of CD8 T-cell tolerance in response to lymphopenia.
abstract: Functional inactivation of self-reactive T lymphocytes contributes to the maintenance of immunologic self-tolerance. At the same time, tolerance induction limits immune responses against tumors expressing tolerizing self-antigens. Some cancer therapies include the adoptive transfer of tumor-reactive T lymphocytes into lymphopenic patients. Lymphopenia provides an activation signal to T lymphocytes, which undergo lymphopenia-induced proliferation (LIP), acquire effector functions, and reject tumors. However, it is so far unknown to which extent LIP may result in reversal of established antigen-specific CD8 T-cell tolerance. Here, we report that neonatally induced dominant CD8 T-cell tolerance remained stable under lymphopenic conditions also in the presence of systemic inflammation induced by Toll-like receptor ligands. However, when lymphopenic recipients were irradiated, the tolerant status was lost, because CD8 T cells acquired effector functions in an interleukin-15-dependent fashion and efficiently rejected tumors. In conclusion, we show that lymphopenia is not sufficient to break CD8 T-cell tolerance. Furthermore, we demonstrate that pretreatment regimens are crucial to circumvent this problem and to optimize adoptive T-cell therapy.
authors.affiliation: Division Molecular Immunology, German Cancer Research Center, Heidelberg, Germany. t.oelert@dkfz.de
authors.forename: Thilo
authors.initials: T
authors.lastname: Oelert
authors.forename: Maria
authors.initials: M
authors.lastname: Papatriantafyllou
authors.forename: Georg
authors.initials: G
authors.lastname: Pougialis
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Thomas
authors.initials: T
authors.lastname: Schüler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects*; D002455:Cell Division / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D006706:Homeostasis / Q000276:immunology / Q000528:radiation effects; D018960:Hyaluronan Receptors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology* / Q000528:radiation effects*; D007249:Inflammation / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D013934:Thymectomy; D014916:Whole-Body Irradiation
chemical_list: D000941:Antigens; D018960:Hyaluronan Receptors; D019409:Interleukin-15