Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8 T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4 CD25 regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8 T cell reactivity to selftissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8 T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

The immune system precisely controls the levels and the activation state of each cellular compartment through homeostatic regulation, a process triggered during development and after the induction of a lymphopenic state (1–7). It has been long observed in mice that depletion of immune cells before adoptive cell transfer (ACT) can considerably enhance the antitumor efficacy of transferred CD8 T cells (8–10). Recently, lymphodepletion followed by ACT has emerged as a promising treatment for patients with metastatic solid cancer (11, 12), but the molecular and cellular mechanisms that contribute to this antitumor effect have not been completely elucidated. Homeostatic expansion