IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects including severe pulmonary edema. Here, we show that IL-2–induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rβγ, including CD8 + T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31 + pulmonary endothelial cells via binding to functional αβγ IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2–mediated pulmonary edema was abrogated by a blocking antibody to IL-2Rα (CD25), genetic disruption of CD25, or the use of IL-2Rβγ–directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Rαβγ + pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rβγ + effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2–based tumor immunotherapy.

BackgroundOne of the big roadblocks in development of HIV-1/AIDS vaccines is the enormous diversity of HIV-1, which could limit the value of any HIV-1 vaccine candidate currently under test.Methodology and FindingsTo address the HIV-1 variation, we designed a novel T cell immunogen, designated HIVCONSV, by assembling the 14 most conserved regions of the HIV-1 proteome into one chimaeric protein. Each segment is a consensus sequence from one of the four major HIV-1 clades A, B, C and D, which alternate to ensure equal clade coverage. The gene coding for the HIVCONSV protein was inserted into the three most studied vaccine vectors, plasmid DNA, human adenovirus serotype 5 and modified vaccine virus Ankara (MVA), and induced HIV-1-specific T cell responses in mice. We also demonstrated that these conserved regions prime CD8+ and CD4+ T cell to highly conserved epitopes in humans and that these epitopes, although usually subdominant, generate memory T cells in patients during natural HIV-1 infection.SignificanceTherefore, this vaccine approach provides an attractive and testable alternative for overcoming the HIV-1 variability, while focusing T cell responses on regions of the virus that are less likely to mutate and escape. Furthermore, this approach has merit in the simplicity of design and delivery, requiring only a single immunogen to provide extensive coverage of global HIV-1 population diversity.

The immune system relies on homeostatic mechanisms in order to adapt to the changing requirements encountered during steady-state existence and activation by antigen. For T cells, this involves maintenance of a diverse repertoire of naïve cells, rapid elimination of effector cells after pathogen clearance, and long-term survival of memory cells. The reduction of T-cell counts by either cytotoxic drugs, irradiation, or certain viruses is known to lead to lymphopenia-induced proliferation and restoration of normal T-cell levels. Such expansion is governed by the interaction of TCR with self-peptide/MHC (p/MHC) molecules plus contact with cytokines, especially IL-7. These same ligands, i.e. p/MHC molecules and IL-7, maintain naïve T lymphocytes as resting cells under steady-state T-cell-sufficient conditions. Unlike naïve cells, typical "central" memory T cells rely on a combination of IL-7 and IL-15 for their survival in interphase and for occasional cell division without requiring signals from p/MHC molecules. Other memory T-cell subsets are less quiescent and include naturally occurring activated memory-phenotype cells, memory cells generated during chronic viral infections, and effector memory cells. These subsets of activated memory cells differ from central memory T cells in their requirements for homeostatic proliferation and survival. Thus, the factors controlling T-cell homeostasis can be seen to vary considerably from one subset to another as described in detail in this review.