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 lymphopeniainduced 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. (Blood. 2010;115: 2196-2202)

Impact of Immune Deficiency on Remodeling of Maternal Resistance Vasculature 4 Weeks Postpartum in Mice

“…Such changes may result from the competition between cells supporting the response of each system and may be related to critical cytokines and growth factors. For example, interleukin 15 is tightly regulated 82 and important for vascular remodeling at the maternal fetal interface 83 for CD8 T-cell homeostasis 84,85 and for tissue-resident T-cell development. 86 Based on these findings herein, and others, 37,50 we speculate that unique interaction between immune and vascular systems is set by the experience of pregnancy and placenta-related factors 87 and continues in PP.…”

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

“…Similar results were obtained in a macaque model where autologous CMV-specific CD8 + T cell clones generated in the presence of IL-15 acquired a central-memory phenotype rather than terminally differentiated effector phenotype and displayed superior persistence (15). Additional findings also demonstrated a role of IL-15 in breaking tolerance and in rescuing tolerant CD8 + T cells for use in adoptive immunotherapy of established tumors (16,17) and in augmenting antigen-specific CD8 + T cells response upon vaccination (18). …”

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

“…All these observations lead us and others to hypothesize that lymphodepletion perturbs the establishment of tolerance. Indeed, it has been recently shown that lymphodepletion promotes the breakdown of peripheral CD8 + T cell tolerance [29, 30]. In this report, we examined the role of systemic LPS translocation in the breakdown of CD8 + T cell cross-tolerance as it occurs in sublethally irradiated InsHA mice.…”

“…However, many different cell populations are still activated in antibiotic treated mice and would be able to produce cytokines at later time points after irradiation. Indeed, the increased availability of cytokines other than IL-7 observed in irradiated mice has been shown to contribute to the gain of effector functions by T cells [30, 57]. Finally, the removal of suppressive populations involved in maintaining T cells under control [15, 57].…”

“…Thus, efficient anti-tumor T cell based immunotherapeutic strategies would need to overcome the mechanisms of peripheral tolerance that prevent self-reactivity [28]. Interestingly, total body irradiation promotes the breakdown of self-tolerance and the development of efficient cytotoxic T lymphocyte (CTL) responses [29, 30]. Indeed, in a mouse model where the influenza virus hemagglutinin (HA) is expressed under the control of the rat insulin promoter in the beta cells of the pancreas, we have previously shown that HA-specific TCR transgenic CD8 + T cells undergo deletional tolerance, even in the presence of antigen-specific CD4 + T helper cells, upon self-antigen cross-presentation [31, 32].…”