Following activation by antigen, naive CD4+ T helper precursor cells execute distinct genetic programs that result in their differentiation toward the type 1 or type 2 helper T cell (Th1 or Th2) phenotype. Although the differentiation and function of these Th subsets has been well studied, little is known about the contribution to these differentiation events of cell surface receptors other than those for soluble cytokines, such as IL-12 or IL-4. Here, we provide direct evidence that the Delta1 interaction with Notch3 on CD4+ T cells transduces signals, promoting development toward the Th1 phenotype. The positive role of Notch signaling in effector cell differentiation was dose dependent, with high levels of stimulation resulting in reduced T cell activation. Our data revealed a clear contribution of Notch pathways to Th1 versus Th2 fate decisions, while also providing insight into another mechanism for inhibition of CD4+ T cell activation.

Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.

CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.

Cancer immunosurveillance is critical for the elimination of neoplastic cells. In addition, recent advances in immunological checkpoint blockade drugs have revealed the importance of the immune system in cancer treatment. As a component of the immune system, CD8+ T cells have important roles in suppressing tumors. CD8+ T cells can kill tumor cells with cytotoxic molecules, such as granzymes and perforin. IFNγ, which is produced by CD8+ T cells, can increase the expression of MHC class I antigens by tumor cells, thereby rendering them better targets for CD8+ T cells. IFNγ also has crucial functions in enhancing the antitumor abilities of other immune cells. Therefore, it has been hypothesized that antitumor immunity could be improved by modulating the activity of CD8+ T cells. The Notch pathway regulates CD8+ T cells in multiple ways. It directly upregulates mRNA expression of granzyme B and perforin, enhances differentiation toward short-lived effector cells, and maintains memory T cells. Intriguingly, CD8+ T cell-specific Notch2 deletion impairs antitumor immunity, whereas the stimulation of the Notch pathway can increase tumor suppression. In this review, we will summarize the roles of the Notch pathway in CD8+ T cells and discuss issues and implications for its use in antitumor immunity.

The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix-PER-ARNT-SIM superfamily. Xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, bind the receptor and trigger diverse biological reactions. Thymocyte development and T cell-dependent immune reactions are sensitive targets of AhR-dependent 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity. However, the exact role of the AhR in T cells in animals exposed to exogenous ligands has not been clarified because indirect effects of activated AhR in other cell types cannot be excluded. In this study, we generated transgenic (Tg) mice expressing a constitutively active mutant of AhR under the regulation of a T cell-specific CD2 promoter to examine AhR function in T cells. The mRNAs of the constitutively active mutant of AhR and an AhR-induced gene, CYP1A1, were expressed in the thymus and spleen of the Tg mice. The transgene expression was clearly detected in the thymocytes, CD4, and CD8 T cells, but not in the B cells or thymus stromal cells. These Tg mice had a decreased number of thymocytes and an increased percentage of CD8 single-positive thymocytes, but their splenocytes were much less affected. By contrast, the increase in number of T cells and B cells taking place in the spleen after immunization was significantly suppressed in the Tg mice. These results clearly show that AhR activation in the T-lineage cells is directly involved in thymocyte loss and skewed differentiation. They also indicate that AhR activation in T cells and not in B cells suppresses the immunization-induced increase in both T cells and B cells.

Fas (APO-1/CD95) is a transmembrane receptor protein which induces apoptosis upon activation. In apoptosis triggered by Fas, a subset of cysteine proteases designated caspases is activated, playing a central role as effector molecules. Among these caspases, human caspase-8 (FLICE/MACH/Mch5) has been isolated and shown to be indispensable for Fas-mediated apoptotic signaling. In this study, we isolated the mouse homologue to human caspase-8 from a BaF3 cell cDNA library. This molecule conserved the death effector domain (DED) and protease domain as detected in human caspase-8, and was capable of inducing apoptosis in KB and Rat-1 cells when overexpressed. Expression of caspase-8 was detected in the various tissues of adult mouse and in embryos at 9.5 days and 17.5 days of development by Northern-blot analysis. Further, we isolated a chromosomal gene for caspase-8 from a mouse genomic library and analyzed the genomic structure of the isolated gene. This gene consisted of eight exons and seven introns spanning about 26 kb in the coding region.Keywords : caspase-8 ; apoptosis; embryo. In Fas-induced and TNFR-1-induced apoptosis, caspase-1-indispensable for apoptotic signaling [7]. The motif of the death domain is also detected in the cytoplasmic region of the tumor like and caspase-3-like activity is reportedly involved [20Ϫ23].Recently, human caspase-8 has been shown to form a complex necrosis factor receptor type I (TNFR-1) and is essential for apoptotic signaling mediated through TNFR-1 [8]. Four novel with Fas and FADD/MORT1 after the ligation of Fas [24Ϫ26].This molecule contains two repeated DED motifs and a protease molecules, FADD/MORT1, RIP, TRADD and MADD, that can interact with the death domains of Fas and/or TNFR-1 have been domain in the N-terminus and C-terminus, respectively, and physically associates with FADD/MORT1 through DED motif isolated using the yeast two-hybrid system [9Ϫ13]. These molecules have a death domain motif in the C-terminal region that interaction. It was suggested that caspase-8 is cleaved into fragments after the formation of the complex, and that the cleaved interacts with the death domain of Fas or TNFR-1, and, with the exception of MADD, they are suggested to transmit the signal C-terminal fragment is further processed and then protease activity appears [24]. for cytocidal effect of Fas and TNFR-1. Among these molecules, FADD/MORT1 reportedly associates with Fas in an activationIn order to study the signal-transduction pathway mediated through Fas in the mouse, we have focused on caspase-8 as an dependent fashion [14] and also forms a complex with TNFR-1 mediated through TRADD [15]. The N-terminal half of FADD/ effector molecule in the apoptotic phase. In the present study, we isolated the cDNA and chromosomal gene for mouse caspase-8, MORT1 shows a novel motif designated the death effector domain (DED). It was shown that FADD/MORT1 lacking the DED characterized expression and killing activity of mouse caspase-8, and analyzed the genomic structure of the mouse gene. motif bec...

The differentiation of naive T cells to effector/memory T cells is regulated by a variety of factors. The recent advance of the contribution of Notch signaling in this differentiation step has provided a new path to better understand the acquisition or persistence of effector function of mature T cells. In this review, we summarize emerging and, in some points, conflicting evidence for Notch signaling on mature T cell activation and differentiation.

T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4−CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4−CD8− (double-negative (DN)) and mature CD4+CD8− (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25− stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.