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• W2023361730 abstract "Notch receptors are widely expressed and have recognized functions in thymocytes and mature T cells. In this issue, Laky et al., 2015Laky K. Evans S. Perez-Diez A. Fowlkes B.J. Immunity. 2015; 42 (this issue): 80-94Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar show that Notch interactions with Delta-like ligand 4 (DLL4) amplify priming of naive T cells. Notch receptors are widely expressed and have recognized functions in thymocytes and mature T cells. In this issue, Laky et al., 2015Laky K. Evans S. Perez-Diez A. Fowlkes B.J. Immunity. 2015; 42 (this issue): 80-94Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar show that Notch interactions with Delta-like ligand 4 (DLL4) amplify priming of naive T cells. There are four mammalian Notch genes, with Notch1, Notch2, and Notch3 known to have important roles in thymopoiesis and the differentiation of CD4+ helper T cells in the periphery (Radtke et al., 2013Radtke F. MacDonald H.R. Tacchini-Cottier F. Nat. Rev. Immunol. 2013; 13: 427-437Crossref PubMed Scopus (274) Google Scholar). Notch receptors are capable of interacting with five ligands, including Jagged1, Jagged2, Delta-like ligand 1 (DLL1), DLL3, and DLL4 (Radtke et al., 2013Radtke F. MacDonald H.R. Tacchini-Cottier F. Nat. Rev. Immunol. 2013; 13: 427-437Crossref PubMed Scopus (274) Google Scholar). Ligation of Notch by its ligands results in proteolytic cleavage of the intracellular domain by gamma secretase. The resulting subunit, according to what is called “canonical signaling,” is trafficked to the nucleus, where it coactivates a number of genes via transcription factors including RBP-Jκ. In noncanonical signaling, the Notch intracellular domain drives the transcription of genes independently of RBP-Jκ. One such route that has shown relevance in Notch-associated T cell leukemias entails direct interaction of the Notch intracellular domain with the NF-κB signaling pathway (Vilimas et al., 2007Vilimas T. Mascarenhas J. Palomero T. Mandal M. Buonamici S. Meng F. Thompson B. Spaulding C. Macaroun S. Alegre M.L. et al.Nat. Med. 2007; 13: 70-77Crossref PubMed Scopus (276) Google Scholar). Effector functions of CD4+ T cells are augmented by Notch signaling, and the pattern of Notch ligands on antigen-presenting cells (APCs) has been shown to drive differentiation of the various T helper (Th) lineages (Radtke et al., 2013Radtke F. MacDonald H.R. Tacchini-Cottier F. Nat. Rev. Immunol. 2013; 13: 427-437Crossref PubMed Scopus (274) Google Scholar). Although its importance in T cell differentiation is well established, the role of Notch signaling in the priming of naive cells is not as well studied. Experiments with gamma-secretase inhibitors (GSIs) have shown that Notch signaling enhances signals of the T cell receptor, resulting in increased expression of activation markers and proliferation (Adler et al., 2003Adler S.H. Chiffoleau E. Xu L. Dalton N.M. Burg J.M. Wells A.D. Wolfe M.S. Turka L.A. Pear W.S. J. Immunol. 2003; 171: 2896-2903Crossref PubMed Scopus (176) Google Scholar, Palaga et al., 2003Palaga T. Miele L. Golde T.E. Osborne B.A. J. Immunol. 2003; 171: 3019-3024Crossref PubMed Scopus (200) Google Scholar). Furthermore, overexpression of the intracellular domain of Notch1 enhances T cell proliferation (Adler et al., 2003Adler S.H. Chiffoleau E. Xu L. Dalton N.M. Burg J.M. Wells A.D. Wolfe M.S. Turka L.A. Pear W.S. J. Immunol. 2003; 171: 2896-2903Crossref PubMed Scopus (176) Google Scholar). In this issue of Immunity, Laky et al., 2015Laky K. Evans S. Perez-Diez A. Fowlkes B.J. Immunity. 2015; 42 (this issue): 80-94Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar add to our knowledge of Notch signaling during the activation of naive T cells with reductionist experiments demonstrating a costimulatory role for Notch-DLL4 interactions in T cell priming. To precisely control activation conditions, Laky et al. transfected CD80+ and CD80− fibroblast lines expressing major histocompatibility complex (MHC) class II glycoproteins and the integrin ICAM-1 with physiological amounts of DLL4. Naive CD4+ T cells showed increased sensitivity to antigen in the presence of DLL4, with enhanced CD69 upregulation and proliferation over a wide range of antigen concentrations. Interestingly, DLL4, which was found to be expressed on a subset of CD11c+ splenic dendritic cells, enhanced T cell activation only if there was concomitant signaling through CD28. Additionally, experiments with mice harboring dendritic cells with conditionally ablated RBP-Jκ demonstrated an absolute requirement for RBP-Jκ in DLL4-mediated upregulation of metabolic genes. Together, these two results suggest an indirect pathway wherein upregulation of RBP-Jκ-dependent genes results in the potentiation of CD28-mediated costimulation (Figure 1). The genes downstream of Notch and RBP-Jκ that enhance glycolysis through the CD28-mediated PI3K signaling pathway are not identified, and future studies will be necessary to further elucidate the pathway connecting Notch signaling with the PI3K-Akt-mTOR pathway. The necessity of CD28 signaling shown here differs from previous work (Adler et al., 2003Adler S.H. Chiffoleau E. Xu L. Dalton N.M. Burg J.M. Wells A.D. Wolfe M.S. Turka L.A. Pear W.S. J. Immunol. 2003; 171: 2896-2903Crossref PubMed Scopus (176) Google Scholar), which revealed that blocking Notch cleavage reduces T cell proliferation when stimulated by beads coated either with both CD3 and CD28 antibodies or CD3 antibody alone. In the work of Adler et al. and other studies, the spontaneous cleavage of Notch upon T cell receptor (TCR) triggering (but in the absence of Notch ligands) is observed but is not well understood. Furthermore, activated T cells may themselves express Notch ligands, including DLL1 (Dongre et al., 2014Dongre A. Surampudi L. Lawlor R.G. Fauq A.H. Miele L. Golde T.E. Minter L.M. Osborne B.A. Front. Immunol. 2014; 5: 54Crossref PubMed Scopus (57) Google Scholar). These findings complicate interpretation of the reductionist studies presented by Laky et al. in their dissection of DLL4-mediated signals into T cells. In addition to enhancing T cell activation, Notch signaling upon ligation by DLL4 also increases the survival of blasting cells by promoting the expression of antiapoptotic factors such as Bcl-2, c-FLIP, and inhibitors of apoptosis (IAPs) (Helbig et al., 2012Helbig C. Gentek R. Backer R.A. de Souza Y. Derks I.A. Eldering E. Wagner K. Jankovic D. Gridley T. Moerland P.D. et al.Proc. Natl. Acad. Sci. USA. 2012; 109: 9041-9046Crossref PubMed Scopus (49) Google Scholar). Thus, Notch signaling amplifies T cell responses through multiple mechanisms. Laky et al. show that a major consequence of DLL4-mediated Notch signaling in naive T cells is to increase cell-surface expression of transferrin receptor and amino acid and glucose (Glut1) transport proteins. The upregulation of these metabolic genes was due to increased activity in the PI3K-Akt-mTOR pathway as measured by phosphorylation of S6, 4EBP1, and GSK3β. These results fit with the well-accepted transition of naive T cells from oxidative phosphorylation to glycolysis during the activation and effector phases. Furthermore, quiescent memory CD4+ T cells, unlike memory CD8+ T cells, require basal glycolysis for survival. Maekawa et al., 2014Maekawa Y. Ishifune C. Tsukumo S. Hozumi K. Yagita H. Yasutomo K. Nat. Med. 2014; (Published online December 15, 2014)https://doi.org/10.1038/nm.3758Crossref PubMed Scopus (99) Google Scholar have recently shown that insulin-mediated upregulation of the glucose transporter Glut1 in memory CD4+ T cells is dependent on RBP-Jκ. This result supports the notion that tonic signaling through Notch is necessary for maintaining a glycolytic metabolic state for memory CD4+ T cells. The principal Notch ligand for supporting memory cells has not been identified, though deletion of DLL1 on CD11c+ dendritic cells results in diminished survival of memory T cells in the bone marrow (Maekawa et al., 2014Maekawa Y. Ishifune C. Tsukumo S. Hozumi K. Yagita H. Yasutomo K. Nat. Med. 2014; (Published online December 15, 2014)https://doi.org/10.1038/nm.3758Crossref PubMed Scopus (99) Google Scholar). These results substantiate the role of Notch signaling into T cells in promoting glycolytic metabolism. The results of Laky et al. are compatible with studies showing a role for Notch in enhancing T cell activation and proliferation (Adler et al., 2003Adler S.H. Chiffoleau E. Xu L. Dalton N.M. Burg J.M. Wells A.D. Wolfe M.S. Turka L.A. Pear W.S. J. Immunol. 2003; 171: 2896-2903Crossref PubMed Scopus (176) Google Scholar, Palaga et al., 2003Palaga T. Miele L. Golde T.E. Osborne B.A. J. Immunol. 2003; 171: 3019-3024Crossref PubMed Scopus (200) Google Scholar), though there is significant disagreement with an earlier reductionist study (Eagar et al., 2004Eagar T.N. Tang Q. Wolfe M. He Y. Pear W.S. Bluestone J.A. Immunity. 2004; 20: 407-415Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Using crosslinking antibodies, Eagar et al. showed that signaling through Notch1 dramatically inhibits T cell activation in response to immobilized CD3 and CD28 antibodies plus either antibodies that crosslink Notch or myc-tagged fusion proteins of Jagged1 or DLL1. It is difficult to reconcile the results of Laky et al. and Helbig et al. with the work of Eagar et al. If organization of Notch ligands is naturally monomeric, it is possible that multivalent ligation of Notch results in diminished activity, either directly (e.g., by unnatural dimerization) or indirectly (e.g., by making less free Notch available for dimerization). The dose of Notch signals seems to be important, too, in that cell-surface ligation with artificial ligands or transduction of T cells with overexpressed Notch intracellular domains may result in aberrant responses. Laky et al. showed an absolute dependence on RBP-Jκ for the Notch-mediated effects on T cell activation and expression of metabolic genes. However, this result is incongruous with recent work showing that in T cells bearing conditionally ablated RBP-Jκ and stimulated with CD3 plus CD28 antibodies, the intracellular domain of Notch1 enhances T cell activation (Dongre et al., 2014Dongre A. Surampudi L. Lawlor R.G. Fauq A.H. Miele L. Golde T.E. Minter L.M. Osborne B.A. Front. Immunol. 2014; 5: 54Crossref PubMed Scopus (57) Google Scholar); in other words, canonical Notch signaling is dispensable for activation of CD4+ T cells. These data indicate that there may be a role for both RBP-Jκ-dependent and noncanonical signals in T cell activation. The specifics of the milieu in which T cells receive activating signals and the phenotype of the APCs are likely to play a dominant role in determining the mode of Notch signaling, as well as the downstream effects. Further experiments will be necessary to resolve these discrepancies. Costimulation is known to play a key role in promoting glucose metabolism during T cell activation (Frauwirth et al., 2002Frauwirth K.A. Riley J.L. Harris M.H. Parry R.V. Rathmell J.C. Plas D.R. Elstrom R.L. June C.H. Thompson C.B. Immunity. 2002; 16: 769-777Abstract Full Text Full Text PDF PubMed Scopus (1012) Google Scholar), and Laky et al. show that Notch-mediated enhancement of costimulation is required for a potent antitumor response. Furthermore, inhibition of Notch controls autoimmunity in an experimental autoimmune encephalomyelitis (EAE) model by decreasing glucose uptake (Maekawa et al., 2014Maekawa Y. Ishifune C. Tsukumo S. Hozumi K. Yagita H. Yasutomo K. Nat. Med. 2014; (Published online December 15, 2014)https://doi.org/10.1038/nm.3758Crossref PubMed Scopus (99) Google Scholar). Thus, modulation of Notch-mediated metabolic switches in T cells could be an important therapeutic tool. In summary, Laky et al. identify a link between Notch, CD28 signaling, and metabolism in peripheral T cells. In so doing, they demonstrate that sensitivity to antigen must be taken down a notch for optimal T cell responses. Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulationLaky et al.ImmunityJanuary 20, 2015In BriefNotch signaling influences effector functions in fully differentiated CD4+ T cells. Laky et al. show that Notch can also enhance T cell activation during the priming phase by increasing the frequency of CD4+ T cells that respond and by improving the quality of the response on a per-cell basis. Full-Text PDF Open Archive" @default.
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• W2023361730 title "Taking T Cell Priming Down a Notch: Signaling through Notch Receptors Enhances T Cell Sensitivity to Antigen" @default.
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