Making room for T cells.

Under conditions of lymphopenia, transferred naive T cells can undergo marked proliferation (1, 2) as a result of both T cell–receptor engagement and cytokine stimulation. Naive T cells that undergo this homeostatic proliferation also acquire characteristics of memory and effector cells as measured by phenotype, by hypersensitivity to antigen stimulation, and by increased production of IFN-γ. This phenomenon has been observed following the adoptive transfer of either naive, transgenic T cells or of polyclonal, wild-type T cells. Recent studies using recombination-activating gene-deficient (Rag–/–) mice, CD3εdeficient mice, and irradiated normal mice as recipients have shown that memory T cells do not revert to naive T cells under these conditions to fill the peripheral naive T cell pool, as originally postulated. Rather, after lymphopenia, homeostasis-driven proliferation restores only the memory T cell compartment, whereas thymopoiesis is required to reconstitute the naive T cell compartment (3, 4). Cytokines and dendritic cells contribute to the induction and maintenance of homeostatic T cell proliferation. Using a coculture system without foreign antigen, Ge et al. (5) demonstrated that such proliferation requires interaction of the T cell receptor with self-peptide MHCs on dendritic cells. In vitro, this response also requires dendritic cell-derived IL-15 and can be inhibited by the introduction of CD4+CD25+ regulatory T cells. In animals recovering from lymphopenia following bone marrow transplantation (BMT), dendritic cells also expedite T cell reconstitution and activation (6, 7). Recent studies show that IL-7 and IL-15 jointly regulate homeostatic proliferation of memory phenotype CD8+ T cells (8, 9), whereas IL-7 on its own enhances naive T cell survival (10). Lymphopenia and antitumor immunity Studies in the late 1970s provided the first evidence that the induction of lymphopenia by sublethal total body irradiation might be beneficial for the treatment of tumors in mice (11). In one such study, irradiation performed 6–8 days after tumor cell injection, when the tumors were first palpable, led in some instances to the complete regression of subcutaneous MCA-1315 tumors in BALB/c mice. Crucially, this total body irradiation did not affect the tumor itself; rather,