Irradiation and IL-15 promote loss of CD8 T-cell tolerance in response to lymphopenia

Functional inactivation of self-reactive T lymphocytes contributes to the maintenance of immunological 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 TLR ligands. However, when lymphopenic recipients were irradiated, the tolerant status was lost, as CD8 T cells acquired effector functions in an IL-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 pre-treatment regimens are crucial to circumvent this problem and optimize adoptive T cell therapy.