Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor γ chain (γc), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-γ production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R−/− mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Despite the existence of morphologically indistinguishable disease, patients with advanced ovarian tumors display a broad range of survival end points. We hypothesize that gene expression profiling can identify a prognostic signature accounting for these distinct clinical outcomes. To resolve survival-associated loci, gene expression profiling was completed for an extensive set of 185 (90 optimal/95 suboptimal) primary ovarian tumors using the Affymetrix human U133A microarray. Cox regression analysis identified probe sets associated with survival in optimally and suboptimally debulked tumor sets at a P value of <0.01. Leave-one-out cross-validation was applied to each tumor cohort and confirmed by a permutation test. External validation was conducted by applying the gene signature to a publicly available array database of expression profiles of advanced stage suboptimally debulked tumors. The prognostic signature successfully classified the tumors according to survival for suboptimally (P = 0.0179) but not optimally debulked (P = 0.144) patients. The suboptimal gene signature was validated using the independent set of tumors (odds ratio, 8.75; P = 0.0146).

Human pancreatic islets are a major focus of diabetes research due to their key role in glucose homeostasis and their potential for transplantation in the treatment of type 1 diabetes. Currently, no comprehensive analysis of baseline or glucose-stimulated islet gene expression is available. Using oligonucleotide microarrays we analyzed isolated intact human islets incubated at low and high glucose. We identified approximately 6000 islet genes, several with clinical implications, as well as a number of glucose-regulated genes. Interestingly, two transforming growth factor beta (TGFbeta) superfamily members were highly regulated by glucose. One of them, PDF, was found to have a very high expression level compared to other TGFbeta superfamily members. Quantitative reverse transcriptase polymerase chain reaction confirmed these results and demonstrated that the highly expressed PDF was approximately 10-fold down- regulated by glucose while other TGFbeta superfamily members and target genes were up-regulated. These results suggest that a highly regulated TGFbeta signaling cascade exists in human islets, and that PDF may play a central role in islet biology. Since TGFbeta is involved in differentiation and immune modulation, this novel pathway may link glucose metabolism, immune response and development of human islets. We report here the first gene expression profile of intact human islets. These and similar analyses will provide better understanding of human islet biology and enhance the development of novel diabetes therapies.