IntroductionConventional TCR ␣␤ cells are exported from the thymus as naive T cells. After activation by exposure to their cognate antigens in the periphery, naive CD4 ϩ ␣␤ T cells differentiate into different helper T-cell lineages such as Th1, Th2, and Th17 cells, depending on the cytokine milieu, which induce different combinations of transcription factors. STAT3, ROR␥t, and ROR␣, which are induced by combined signals from TGF␤ and IL-6 receptors, play important roles in the differentiation of Th17 cells by binding to the promoter or the enhancer region of the IL17 gene. 1-3 STAT3 also inhibits the expression of Foxp3, which suppresses the functions of ROR␥t. 4 In addition to Th17 cells, several subsets of T cells produce IL-17. These include T cells lacking CD4 and CD8, CD8 ϩ T cells, invariant natural killer T cells (NKT cells), and TCR ␥␦ T cells. [5][6][7][8] There is accumulating evidence that TCR ␥␦ T cells could be the major source of IL-17 in various murine models of infection such as Mycobacterium tuberculosis, Escherichia coli, and Listeria monocytogenes. 9 IL-17-producing ␥␦ T cells are also involved in the pathogenesis of autoimmune diseases such as experimental allergic encephalomyelitis, collagen-induced arthritis, chronic granulomatous disease, and ischemic brain injury. 10 Interestingly, even freshly isolated ␥␦ T cells from the thymus produce IL-17 in response to phorbol myristate acetate (PMA) and ionomycin stimulation, indicating the functional differentiation within the thymus. 11 Such naturally occurring IL-17-producing ␥␦ T cells were already detected at the fetal stage as early as on embryonic day 15 (E15), when ␥␦ T cells began to develop. 11 Therefore, in ␥␦ T cells, the development and functional differentiation to IL-17 producers coincidentally occur within the fetal thymus. Intrathymic functional differentiation has been well documented for NKT cells. 12 During intrathymic development, NKT cell precursors acquire either an IL-4-or an IFN-␥-producing function at different stages. 13 Furthermore, there is a population of NKT cells that differentiates into IL-17-producing cells in the thymus independently of 14 Nevertheless, like Th17 cells, IL-17-producing NKT cells require ROR␥t for their development. 15 At present, the molecular mechanisms for the development of IL-17-producing ␥␦ T cells have not been defined, although it has been shown that IL-17-producing ␥␦ T cells developed normally in IL-6-deficient mice but were decreased in the absence of TGF-␤1. 16,17 In the present study, we found that Hes1, one of the basic helix-loop-helix (bHLH) proteins induced by Notch signaling, was specifically expressed in IL-17-producing ␥␦ T cells. Furthermore, Hes1, rather than STAT3 and ROR␥t, was critically involved in intrathymic development of IL-17-producing ␥␦ T cells. Expression of Hes1 is also important for IL-17 production by ␥␦ T cells in the periphery. Therefore, although Notch signaling is well known for its role in thymocyte development, it also regulates innate functions of ␥␦ T c...

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand‐independent manner via Plexin B1. SEMA3C expression levels increase in castration‐resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide‐resistant progression. Plexin B1 sema domain‐containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post‐castration in vivo. SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

Interleukin-17A (IL-17A)-producing ␥␦ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring ␥␦ T cells play a protective role in the lung at a very early stage after systemic infection with Candida albicans. Selective depletion of neutrophils by in vivo administration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection with C. albicans.

T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.