T cell development ͉ T cell differentiation ͉ T cell signaling T he Tec family tyrosine kinase Itk is important for signaling downstream of the T cell receptor (1). In particular, Itkdeficient T cells have defects in phospholipase C-␥ (PLC-␥) phosphorylation, calcium mobilization, mitogen-activated protein kinase (MAP kinase) activation, and AP-1 and nuclear factor of activated T cells (NFAT) activation after T cell receptor (TCR) stimulation. Itk is also critical for conventional ␣␤ T cell development, selection, and function. Of particular importance, Itk signaling regulates CD4 ϩ T helper cell differentiation, playing a key role in the development of Th2 responses (2). Based on this welldocumented defect of Itk Ϫ/Ϫ mice in generating Th2 effector responses and cytokine production, it was surprising to discover that these mice had spontaneously elevated levels of serum IgE (3, 4), as B cell isotype switching to IgE is highly dependent on Th2 cytokines IL-4 and IL-13 (5). As our previous studies had indicated that Itk Ϫ/Ϫ ␣␤ TCR ϩ NKT cells (referred to as ␣␤ NKT cells) were also highly defective in producing effector cytokines such as IL-4 (6), we considered the possibility that ␥␦ TCR ϩ NKT cells were the major source of Th2 cytokines in Itk Ϫ/Ϫ mice.The ␥␦ T cells are a highly conserved subset of T cells that constitutes 1-5% of the lymphocytes in the blood and peripheral organs of mice but can account for up to 50% of the lymphocytes in the mucosal epithelia. As with other subsets of ''innate'' T cells, ␥␦ T cells express memory cell surface markers (7), and are capable of rapidly secreting effector cytokines (8). Among the many functions attributed to ␥␦ T cells, a great deal of recent interest has focused on their ability to modulate adaptive immune responses, specifically the humoral response (9).A variety of studies have indicated that ␥␦ T cells are able to provide help for B cell responses. Initial studies performed in mice lacking ␣␤ T cells showed that B cell expansion, differentiation, and secretion of 'T-dependent' antibody isotypes, IgE, and IgG 1 , were all intact in these mice (10). Furthermore, TCR␤ Ϫ/Ϫ mice challenged repeatedly with parasitic infections could produce germinal centers and generate increased antibody production (11). Using a model of pulmonary allergic inflammation, decreased production of IgE and IgG 1 was seen in mice lacking ␥␦ T cells compared with WT mice (12). The ␥␦ T cells have also been shown to directly induce germinal center formation and Ig hypermutation (13). Interestingly, even though the ␥␦ T cells expressing CD4 account for only 5-10% of all ␥␦ cells, it is this subset that appears to be responsible for inducing germinal centers (14). Human ␥␦ T cells have also been found in germinal centers; these cells were found to up-regulate B cell costimulatory molecules such as CD40L, OX40, CD70, and inducible costimulatory molecule (ICOS) in response to TCR stimulation (15, 16). Together, these data indicate that ␥␦ T cells can promote, either directly or indirectly, th...

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

No abstract

No abstract