Lymphopenia enhances the effectiveness of adoptive immunotherapy by facilitating expansion of transferred T cells but also limits the T-cell repertoire available to mediate immune responses and, in humans, is associated with chronic immune dysfunction. Previous studies concluded that
lymphopenia augments adoptive immunotherapy by diminishing Tregs and increasing homeostatic
cytokines. We sought to determine whether targeted
therapies that replicate the physiology of
lymphopenia in lymphoreplete hosts could provide a similarly supportive milieu. Pmel-1 T cells were transferred to B16-bearing lymphopenic versus lymphoreplete mice receiving alphaCD25 and/or recombinant human
interleukin-7. Although CD25-based Treg depletion was inefficient because of peripheral expansion of CD4+CD25-FOXP3+ cells, outcomes were better in alphaCD25-treated lymphoreplete hosts than in lymphopenic hosts, and adoptive immunotherapy was most effective in lymphoreplete hosts receiving alphaCD25 plus recombinant human
interleukin-7. Lymphopenic hosts supported increased proliferation of adoptively transferred
antigen-specific T cells, but cells transferred to lymphoreplete recipients receiving targeted
therapies showed superior function. Further, determinant spreading was substantial in lymphoreplete hosts but absent in lymphopenic hosts. These results demonstrate that targeted
therapies delivered to mimic the "physiology of
lymphopenia" enhance the efficacy of adoptive immunotherapy in lymphoreplete hosts and provide a potentially superior alternative to the induction of
lymphopenia.