Notch signaling maintains T cell memories - Nature

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volume 21 | number 1 | January 2015 NATURE MEDICINE the radio wave or magnetic field signal into intracellular signals other than Ca2+. A further inherent ...
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news and views the radio wave or magnetic field signal into intracellular signals other than Ca2+. A further inherent advantage of a genetically encoded switch over a nongenetic system such as delivery of exogenously derived nanoparticles is the possibility of tissue- or cell type–specific expression, by using appropriate promoter elements to drive transcription. This would restrict the expression and action of the switch to the tissue or cell type of interest and thereby reduce side effects as a result of expression in unwanted tissues or cells. Interestingly, the fact that Stanley et al.3 can also activate the switch by a magnetic field suggests that an applied oscillatory magnetic field could be converted into an oscillatory [Ca2+]i pattern. If this were to be the case, modulating the frequency of [Ca2+]i oscillations would allow the regulation of discrete downstream targets that are distinctly regulated by different [Ca2+]i frequencies, such as insulin secretion, insulin gene expression and pancreatic beta cell survival7–9.

It is feasible to combine the noninvasive modulation of gene expression now described by Stanley et al.3 with noninvasive monitoring systems to assess efficiency of expression, or study the effects of the expressed molecule within its target tissue. For example, engraftment of a sample of deep tissue, such as the pancreatic islets, in the anterior chamber of the eye allows for noninvasive, longitudinal imaging of pancreatic islet or beta cell function by fluorescence microscopy10,11. Hence, the immediate effects of biomolecules expressed by the remote control system described by Stanley et al.3 could be efficiently evaluated with regard to for example in situ pancreatic islet cell function and survival by reporter islets in the eye (Fig. 1b). This may be a valuable tool for investigating the efficacy of a novel personalized medicine approach. A genetically encoded switch to control biological systems in the living organism by either low-frequency radio waves or by

a magnetic field is an exciting noninvasive approach with many potential applications. Time will tell if this is the beginning of a new era of radiogenetics and magnetogenetics, which could potentially prove to be even more versatile than optogenetics. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Gossen, M. et al. Science 268, 1766–1769 (1995). 2. Danielian, P.S. et al. Curr. Biol. 8, 1323–1326 (1998). 3. Stanley, S.A., Sauer, J., Dordick, J.S. & Friedman, J.M. Nat. Med. 21, 92–98 (2015). 4. Stanley, S.A. et al. Science 336, 604–608 (2012). 5. Gilles, C. et al. J. Magn. Magn. Mater. 241, 430–440 (2002). 6. Liedtke, W. et al. Cell 103, 525–535 (2000). 7. Smedler, E. & Uhlen, P. Biochim. Biophys. Acta 1840, 964–969 (2014). 8. Berggren, P.O. et al. Cell 119, 273–284 (2004). 9. Li, L. et al. Diabetes 63, 4100–4114 (2014). 10. Speier, S. et al. Nat. Med. 14, 574–578 (2008). 11. Ilegems, E. et al. Proc. Natl. Acad. Sci. USA 110, 20581–20586 (2013).

Notch signaling maintains T cell memories Aaron M Miller & Stephen P Schoenberger Notch signaling regulates developmental processes. A new study in mice shows that Notch signaling regulates the maintenance and survival of memory CD4+ T lymphocytes through a mechanism involving glucose uptake, and it suggests that Notch signaling can be modulated to treat autoimmune conditions. The adaptive arm of the immune system, comprising B and T lymphocytes, must generate responses of appropriate specificity, type, and magnitude to counter infectious pathogens, and then ensure that a cohort of memory cells can persist long enough to protect from possible reencounter. CD4+ T lymphocytes are key to both processes; they are direct effectors and activate other immune cells in addition to helping establish a memory state in B and CD8+ T cells1. But memory cells have also been implicated in both the cause and the resolution of human diseases such as type I diabetes and multiple sclerosis, and there is interest in understanding the mechanisms that enable their longevity over that of short-lived effectors that could otherwise contribute to persistent inflammation2,3. Aaron M. Miller and Stephen P. Schoenberger are at the Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology and the Division of Hematology and Oncology, Moores Cancer Center, The University of California, San Diego, San Diego, California, USA. e-mail: [email protected]

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Compared with CD8+ T cells, less is known about the features of CD4+ T cell memory and the pathways that regulate their activities. This is partially due to the modest magnitude of the immune response of CD4+ T cells. The understanding of CD4+ T cell memory has also been hampered by the relative paucity of clearly defined phenotypic markers for memory T cells versus activated CD4+ T cells. Notch signaling has a role in the intrathymic survival of pre-T cells, as well as in the survival of mature CD4+ T cells, as suggested by work showing that mature mouse Notch-deficient cells displayed an increased sensitivity to apoptosis induction4,5. The Notch pathway is an evolutionarily conserved signaling pathway that regulates cell fate through local intercellular interactions6. The Notch transmembrane receptor is cleaved following interaction with a canonical Notch transmembrane ligand on a contacting cell to liberate the Notch intracellular domain (NICD). The NICD then translocates to the nucleus, where in mammals it interacts with the Notch signaling proteins Rbpj and p300 to initiate transcription of Notch

target genes7. In this issue of Nature Medicine, Maekawa et al.8 provide evidence that Notch has a role in ensuring the survival of activated CD4+ T cells and their development into memory cells. Maekawa et al.8 first immunized mice in which Rbpj had been selectively deleted in CD4+ cells. They found that the proliferative response of Rbpj-deficient CD4+ T cells to primary immunization was largely indistinguishable from that of the wild-type control CD4+ T cells, but that numbers of the Ly6Cexpressing Rbpj-deficient CD4+ T cell subset— that is thought to contain the memory population—decreased over time8. Remarkably, the surviving memory CD4+ T cells lacking Rbpj were capable of proliferating in response to secondary challenge, indicating that Notch signaling did not affect this aspect of memory functionality (Fig. 1a). However, in a delayed type hypersensitivity assay that assesses memory responses, memory CD4+ T cells lacking Rbpj mounted a diminished secondary response against Leishmania major after challenge further supporting a role for Notch in memory

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Marina Corral Spence/Nature Publishing Group

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Rbpj–/– Notch1–/– or Notch2–/– WT + GSI

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Figure 1 Notch signaling is required for maintenance of memory CD4+ T cells. (a) Maekawa et al.8 show that CD4+ T cells deficient in Notch signaling due to chemical inhibition by GSI, or to a lack of Rbpj, Notch1, or Notch2, proliferate in response to immune priming, but they show decreased survival and diminished responses to secondary challenge. (b) Maekawa et al.8 also find that upon priming by antigen-presenting cells (APCs, green), inactive CD4 + T cells (blue) are activated (pink), and that those activated T cells that receive Notch signaling (purple) from APCs in the bone marrow have insulin-induced expression of the Glut1 transporter, thereby prolonging their survival into memory cells capable of secondary responses. WT, wild type.

CD4+ T cell survival. Furthermore, condi­ tional knockouts of Notch1 and Notch2, alone or in combination, in CD4+ cells indicated that both receptors were involved in the survival of activated or memory CD4+ T cells. The authors’ data also suggests that the Notch ligand signaling to these cells is Dll1 on CD11c+ dendritic cells (antigen presenting cells)8. To better define the role of Notch signaling in the memory response, Maekawa et al.8 immunized mice with a hapten–protein antigen, NP-KLH, and then treated mice 60 days later with a γ-secretase inhibitor (GSI), LY-411575 (which prevents cleavage of the

Notch receptor) for four days before reexposing mice to NP-KLH two days later. They found that GSI-treated mice produced less total and less high-affinity anti-NP IgG than their DMSO-treated control counterparts, supporting the idea that secondary responses were directly affected by the treatment8. Furthermore, transfer of CD4+ T cells from NP-KLH–immunized control mice coincident with the secondary challenge restored IgG to control levels even in the presence of GSI. Taken together, these findings suggested that, assuming that the only target of GSI is the Notch signaling pathway, Notch signals regulate the survival of memory cells.

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The authors then tested whether Notchmediated memory regulation is involved in autoimmune disease development in a model of organ-specific autoimmunity, experimental autoimmune encephalomeyltitis (EAE), in which myelin oligodendrocyte glycoprotein (MOG) peptide-specific CD4+ T cells are adoptively transferred and mediate transitory paralysis following transfer, and again after challenge with the relevant MOG peptide8. Maekawa et al.8 found that treatment of mice with GSI 45 days after their initial EAE resolved reduced the number of MOGspecific CD4+ T cells in the recipients and completely prevented the secondary induction of disease after MOG challenge. As in the NP-KLH system, transfer of memory CD4+ T cells from MOG-immunized mice just before secondary challenge of the GSI-treated cohort restored the induction of EAE, supporting the idea that GSI specifically affects the survival of the memory subset of CD4+ T cells, rather than some other populations within the treated animals. To better define the molecular mechanisms underlying the role of Notch, Maekawa et al.8 first looked to several of the most likely candidate genes and pathways affecting the survival of CD4+ T cells. They found no evidence for T cell exhaustion or for a mechanism mediated by apoptosis, by Stat5 or mTOR signaling, or by Mcl1 or IL-7 signaling8. Turning their attention to metabolic control of survival, Maekawa et al.8 found that in mice Rbpj-deficient CD4+ T cells took up less glucose than their wild-type counterparts at late time points (day 16) after OVA immunization. To confirm defective glucose uptake in Rbpj-deficient memory CD4+ T cells, Maekawa et al.8 injected the immunized mice with sodium pyruvate, which bypasses glycolysis and is a substrate for the tricarboxylic acid cycle (Fig. 1). Pyruvate injection decreased the magnitude of CD4+ T cell numerical decline. In the EAE model, they found that both the survival of MOGspecific-CD4+ T cells and their ability to cause EAE were enhanced by pyruvate treatment8. Notably, pyruvate also increased the ability of MOG-specific CD4+ T cells to survive and cause disease in DMSO-treated control mice, suggesting that its effects on CD4+ T cells may merit further investigation. Insulin regulates the transport of glucose by inducing the expression of glucose transporters involved in the uptake of environmental glucose. Maekawa et al.8 showed that the insulin-induced expression of the Glut1 glucose transporter was reduced in Rbpjdeficient CD4+ T cells, as was the ability of these cells to mediate aerobic glycolysis following insulin exposure, as measured by 17

extracellular acidification. A role for Akt in the defective insulin-mediated induction of Glut1 expression in Rbpj-deficient CD4+ T cells was noted by the finding that such cells expressed lower levels of activated Akt than wild-type controls in response to insulin, and that expression of constitutively active Akt could restore both glucose uptake and enhance cellular survival8. The authors’ data indicates that Notch is key in T cell maintenance at late time points following activation, and therefore in the ability of T cells to develop into memory cells8. Furthermore, they show that CD4+ T cells retain a durable dependence on Notch signals for long periods after their primary expansion but can undergo a normal immune recall response, suggesting that it is the capacity of CD4+ T cells to survive rather than their intrinsic ability to manifest key functional capacities associated with immune memory that is affected by Notch signals8. This contrasts with the role of Notch in CD8+ T cells; recent evidence has revealed this pathway to be instrumental in determining whether cells will follow the effector or the memory developmental program9.

The finding regarding defective glucose uptake and aerobic glycolysis in Notchdeficient CD4+ T cells is surprising in light of numerous studies showing that CD8+ memory T cells depend more on fatty acid oxidation (FAO) and oxidative phosphorylation than on glycolysis for their energetic requirements10. The lack of unambiguous surface markers with which to define the memory subset in CD4+ T cells makes it difficult to determine which cells are affected by the absence of Notch, but the recent finding that CD8+ memory T cells take up glucose from their environment to synthesize fatty acids which are then catabolized through cell-intrinsic lipolysis makes a parallel mechanism in CD4+ T cells attractive11. However, Maekawa et al.8 report no differences in the expression level of genes involved in FAO, but they did not report on the expression of lysosomal acid lipase, which is involved in energy homeostasis of CD8+ memory T cells in peripheral compartments. The finding that the Notch pathway could be a ‘druggable target’ for ameliorating autoimmune pathology caused by CD4+ T cells is notable and could open up new possibilities for therapeutic intervention, as has been done for aberrant Notch signaling in a variety of

diseases12. The effectiveness of these interventions must naturally be considered in light of their well-known negative side effects, but development of the appropriate dose and frequency regimen for effective management of the episodic behavior of CD4+ T cells in many human autoimmune diseases presents an especially laudable goal13. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Zhu, J., Yamane, H. & Paul, W.E. Annu. Rev. Immunol. 28, 445–489 (2010). 2. Mueller, S.N., Gebhardt, T., Carbone, F.R. & Heath, W.R. Annu. Rev. Immunol. 31, 137–161 (2013). 3. Devarajan, P. & Chen, Z. Immunol. Res. 57, 12–22 (2013). 4. Ciofani, M. & Zuniga-Pflucker, J.C. Nat. Immunol. 6, 881–888 (2005). 5. Helbig, C. et al. Proc. Natl. Acad. Sci. USA 109, 9041–9046 (2012). 6. Andersson, E.R., Sandberg, R. & Lendahl, U. Development 138, 3593–3612 (2011). 7. Artavanis-Tsakonas, S., Rand, M.D. & Lake, R.J. Science 284, 770–776 (1999). 8. Maekawa, Y. et al. Nat. Med. 21, 55–61 (2015). 9. Backer, R.A. et al. Nat. Immunol. 15, 1143–1151 (2014). 10. Pearce, E.L., Poffenberger, M.C., Chang, C.H. & Jones, R.G. Science 342, 1242454 (2013). 11. O’Sullivan, D. et al. Immunity 41, 75–88 (2014). 12. Andersson, E.R. & Lendahl, U. Nat. Rev. Drug Discov. 13, 357–378 (2014). 13. Tolcher, A.W. et al. J. Clin. Oncol. 30, 2348–2353 (2012).

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volume 21 | number 1 | January 2015 nature medicine