Regulation of T Cell Activation and Metabolism by Transforming Growth Factor-Beta
Abstract
:Simple Summary
Abstract
1. Introduction
2. Overview of T Cell Metabolism
3. Fundamentals of TGFβ Signalling
4. TGFβ Modulation of T Cell Activation and Metabolism
4.1. T Cell Differentiation Is Accompanied by and Dependent upon Metabolic Reprogramming
4.2. TGFβ Modulates Treg Metabolism via FoxP3-Dependent and Independent Effects
4.3. Modulation of Glycolytic Metabolism during Th9 Differentiation by TGFβ
4.4. Effects of TGFβ on Effector CD4+ T Cell Metabolism
4.5. Impact of TGFβ on CD8+ T Cell Activation and Metabolism
4.6. Regulation of T Cell Exhaustion
4.7. Effects of TGFβ on Memory T Cell Formation and Metabolism
4.8. TGFβ Modulation of Metabolism during T Cell Anti-Tumour Immunity
5. Conclusions and Future Prospects
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Batlle, E.; Massagué, J. Transforming growth factor-β signalling in immunity and cancer. Immunity 2019, 50, 924–940. [Google Scholar] [CrossRef] [PubMed]
- Chen, B.; Mu, C.; Zhang, Z.; He, X.; Liu, X. The love-hate relationship between TGF-β signalling and the immune system during development and tumorigenesis. Front. Immunol. 2022, 13, 891268. [Google Scholar] [CrossRef] [PubMed]
- Nixon, B.G.; Gao, S.; Wang, X.; Li, M.O. TGFβ control of immune responses in cancer: A holistic immuno-oncology perspective. Nat. Rev. Immunol. 2022. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
- Macintyre, A.N.; Gerriets, V.A.; Nichols, A.G.; Michalek, R.D.; Rudolph, M.C.; Deoliveira, D.; Anderson, S.M.; Abel, E.D.; Chen, B.J.; Hale, L.P.; et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014, 20, 61–72. [Google Scholar] [CrossRef] [PubMed]
- Sinclair, L.V.; Rolf, J.; Emslie, E.; Shi, Y.B.; Taylor, P.M.; Cantrell, D.A. Antigen receptor control of amino acid transport coordinates the metabolic reprogramming that is essential for T cell differentiation. Nat. Immunol. 2013, 14, 500–508. [Google Scholar] [CrossRef]
- Nakaya, M.; Xiao, Y.; Zhou, X.; Chang, J.H.; Chang, M.; Cheng, X.; Blonska, M.; Lin, X.; Sun, S.C. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014, 40, 692–705. [Google Scholar] [CrossRef]
- Patra, K.C.; Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 2014, 39, 347–354. [Google Scholar] [CrossRef]
- Berod, L.; Friedrich, C.; Nandan, A.; Freitag, J.; Hagemann, S.; Harmrolfs, K.; Sandouk, A.; Hesse, C.; Castro, C.N.; Bähre, H.; et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 2014, 20, 1327–1333. [Google Scholar] [CrossRef]
- O’Sullivan, D.; van der Windt, G.; Huang, S.C.C.; Curtis, J.D.; Chang, C.H.; Buck, M.D.; Qiu, J.; Smith, A.M.; Lam, W.Y.; DiPlato, L.M.; et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 2014, 41, 75–88. [Google Scholar] [CrossRef]
- Sena, L.A.; Li, S.; Jairaman, A.; Prakiya, M.; Ezponda, T.; Hildeman, D.A.; Wang, C.R.; Schumacker, P.T.; Licht, J.D.; Perlman, H.; et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013, 38, 225–236. [Google Scholar] [CrossRef]
- Wang, R.; Dillon, C.P.; Shi, L.Z.; Milasta, S.; Carter, R.; Finkelstein, D.; McCormick, L.L.; Fitzgerald, P.; Chi, H.; Munger, J.; et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011, 35, 871–882. [Google Scholar] [CrossRef]
- Polizzi, K.N.; Powell, J.D. Regulation of T cells by mTOR: The known knowns and the known unknowns. Trends Immunol. 2015, 36, 13–20. [Google Scholar] [CrossRef]
- Man, K.; Kallies, A. Synchronizing transcriptional control of T cell metabolism and function. Nat. Rev. Immunol. 2015, 15, 574–584. [Google Scholar] [CrossRef]
- Salmond, R.J. mTOR regulation of glycolytic metabolism in T cells. Front. Cell Dev. Biol. 2018, 6, 122. [Google Scholar] [CrossRef]
- Marchingo, J.M.; Sinclair, L.V.; Howden, A.J.; Cantrell, D.A. Quantitative analysis of how Myc controls T cell proteome and metabolic pathways during T cell activation. eLife 2020, 9, e53725. [Google Scholar] [CrossRef]
- Shi, L.Z.; Wang, R.; Huang, G.; Vogel, P.; Neale, G.; Green, D.R.; Chi, H. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 2011, 208, 1367–1376. [Google Scholar] [CrossRef]
- Finlay, D.K.; Rosenzweig, E.; Sinclair, L.V.; Feijoo-Carnero, C.; Hukelmann, J.L.; Rolf, J.; Panteleyev, A.A.; Okkenhaug, K.; Cantrell, D.A. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 2012, 209, 2441–2453. [Google Scholar] [CrossRef]
- Michalek, R.D.; Gerriets, V.A.; Nichols, A.G.; Inoue, M.; Kazmin, D.; Chang, C.Y.; Dwyer, M.A.; Nelson, E.R.; Polizzi, K.N.; Ilkayeva, O.; et al. Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. USA 2011, 108, 18348–18353. [Google Scholar] [CrossRef]
- Kidani, Y.; Elsaesser, H.; Hock, M.B.; Vergnes, L.; Williams, K.J.; Argus, J.P.; Marbois, B.N.; Komisopoulous, E.; Wilson, E.B.; Osborne, T.F.; et al. Sterol regulatory element-binding proteins are essential for the metabolic reprogramming of effector T cells and adaptive immunity. Nat. Immunol. 2013, 14, 489–499. [Google Scholar] [CrossRef]
- Buck, M.D.; Sowell, R.T.; Kaech, S.M.; Pearce, E.L. Metabolic instruction of immunity. Cell 2017, 169, 570–586. [Google Scholar] [CrossRef]
- Klein Geltink, R.I.; Kyle, R.L.; Pearce, E.L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 2018, 36, 461–488. [Google Scholar] [CrossRef] [PubMed]
- Makowski, L.; Chaib, M.; Rathmell, J.C. Immunometabolism: From basic mechanisms to translation. Immunol. Rev. 2020, 295, 5–14. [Google Scholar] [CrossRef] [PubMed]
- Steinert, E.M.; Vasan, K.; Chandel, N.S. Mitochondrial metabolism regulation of T cell-mediated immunity. Annu. Rev. Immunol. 2021, 39, 395–416. [Google Scholar] [CrossRef] [PubMed]
- Nolte, M.; Margadant, C. Controlling immunity and inflammation through integrin-dependent regulation of TGF-β. Trends Cell Biol. 2020, 30, 49–59. [Google Scholar] [CrossRef] [PubMed]
- Aashaq, S.; Batool, A.; Mir, S.A.; Beigh, M.A.; Andrabi, K.I.; Shah, Z.A. TGF-β signalling: A recap of SMAD-independent and SMAD-dependent pathways. J. Cell Physiol. 2022, 237, 59–85. [Google Scholar] [CrossRef] [PubMed]
- Shull, M.M.; Ormsby, I.; Kier, A.B.; Pawlowski, S.; Diebold, R.J.; Yin, M.; Allen, R.; Sidman, C.; Proetzel, G.; Calvin, D.; et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 1992, 359, 693–699. [Google Scholar] [CrossRef]
- Gorelik, L.; Flavell, R.A. Abrogation of TGFbeta signalling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000, 12, 171–181. [Google Scholar] [CrossRef]
- Marie, J.C.; Liggitt, D.; Rudensky, A.Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006, 25, 441–454. [Google Scholar] [CrossRef]
- Gu, A.D.; Wang, Y.; Lin, L.; Zhang, S.S.; Wan, Y.Y. Requirements of transcription factor Smad-dependent and -independent TGF-β signalling to control discrete T-cell functions. Proc. Natl. Acad. Sci. USA 2012, 109, 905–910. [Google Scholar] [CrossRef]
- Kotlarz, D.; Marquardt, B.; Barøy, T.; Lee, W.S.; Konnikova, L.; Hollizeck, S.; Magg, T.; Lehle, A.S.; Walz, C.; Borggraefe, I.; et al. Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat. Genet. 2018, 50, 344–348. [Google Scholar] [CrossRef]
- Gorelik, L.; Constant, S.; Flavell, R.A. Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 2002, 195, 1499–1505. [Google Scholar] [CrossRef]
- Gorelik, L.; Fields, P.E.; Flavell, R.A. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA3 expression. J. Immunol. 2000, 165, 4773–4777. [Google Scholar] [CrossRef]
- Veldhoen, M.; Hocking, R.J.; Atkins, C.J.; Locksley, R.M.; Stockinger, B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006, 24, 179–189. [Google Scholar] [CrossRef]
- Schmitt, E.; Germann, T.; Goedert, S.; Hoehn, P.; Huels, C.; Koelsch, S.; Kühn, R.; Müller, W.; Palm, N.; Rüde, E. IL-9 production of naïve CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J. Immunol. 1994, 153, 3989–3996. [Google Scholar] [CrossRef]
- Veldhoen, M.; Uyttenhove, C.; van Snick, J.; Helmby, H.; Westendorf, A.; Buer, J.; Martin, B.; Wilhelm, C.; Stockinger, B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 2008, 9, 1341–1346. [Google Scholar] [CrossRef]
- Dardalhon, V.; Awasthi, A.; Kwon, H.; Galileos, G.; Gao, W.; Sobel, R.A.; Mitsdoerffer, M.; Strom, T.B.; Elyaman, W.; Ho, I.C.; et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat. Immunol. 2008, 9, 1347–1355. [Google Scholar] [CrossRef]
- Eyerich, S.; Eyerich, K.; Pennino, D.; Carbone, T.; Nasorri, F.; Pallotta, S.; Cianfarani, F.; Odorisio, T.; Traidl-Hoffmann, C.; Behrendt, H.; et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodelling. J. Clin. Investig. 2009, 119, 3573–3585. [Google Scholar] [CrossRef]
- Rutz, S.; Noubade, R.; Eidenschenk, O.N.; Zeng, W.; Zheng, Y.; Hackney, J.; Ding, J.; Singh, H.; Ouyang, W. Transcription factor c-Maf mediates the TGF-β-dependent suppression of IL-22 production in T(H)17 cells. Nat. Immunol. 2011, 12, 1238–1245. [Google Scholar] [CrossRef]
- Perez, L.G.; Kempski, J.; McGee, H.M.; Pelzcar, P.; Agalioti, T.; Giannou, A.; Konczalla, L.; Brockmann, L.; Wahib, R.; Xu, H.; et al. TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat. Commun. 2020, 11, 2608. [Google Scholar] [CrossRef]
- Schmitt, N.; Liu, Y.; Bentebibel, S.E.; Munagala, I.; Bourdery, L.; Venuprasad, K.; Banchereau, J.; Ueno, H. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat. Immunol. 2014, 15, 856–865. [Google Scholar] [CrossRef]
- Chaurio, R.A.; Anadon, C.M.; Costich, T.L.; Payne, K.K.; Biswas, S.; Harro, C.M.; Moran, C.; Ortiz, A.C.; Cortina, C.; Rigolizzo, K.E.; et al. TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intratumoral tertiary lymphoid structures. Immunity 2022, 55, 115–128. [Google Scholar] [CrossRef] [PubMed]
- Stephen, T.L.; Payne, K.K.; Chaurio, R.A.; Allegrezza, M.J.; Zhu, H.; Perez-Sanz, J.; Perales-Puchalt, A.; Nguyen, J.M.; Vara-Ailor, A.E.; Eruslanov, E.B.; et al. SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 2017, 46, 51–64. [Google Scholar] [CrossRef] [PubMed]
- Zheng, S.G.; Gray, J.D.; Ohtsuka, K.; Yamagiwa, S.; Horwitz, D.A. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25− precursors. J. Immunol. 2002, 169, 4183–4189. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral CD4+CD25− naïve T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198, 1875–1886. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Zhang, P.; Li, J.; Kulkarni, A.B.; Perruche, S.; Chen, W. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 2008, 9, 632–640. [Google Scholar] [CrossRef]
- Lückel, C.; Picard, F.S.R.; Huber, M. Tc17 biology and function: Novel concepts. Eur. J. Immunol. 2020, 50, 1257–1267. [Google Scholar] [CrossRef]
- Schnell, A.; Littman, D.R.; Kuchroo, V.K. TH17 cell heterogeneity and its role in tissue inflammation. Nat. Immunol. 2023, 24, 19–29. [Google Scholar] [CrossRef]
- Michalek, R.D.; Gerriets, V.A.; Jacobs, S.R.; Macintyre, A.N.; MacIver, N.J.; Mason, E.F.; Sullivan, S.A.; Nichols, A.G.; Rathmell, J.C. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 2011, 186, 3299–3303. [Google Scholar] [CrossRef]
- Wang, Y.; Bi, Y.; Chen, X.; Li, C.; Li, Y.; Zhang, Z.; Wang, J.; Lu, Y.; Yu, Q.; Su, H.; et al. Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4+ T cells. Immunity 2016, 44, 1337–1349. [Google Scholar] [CrossRef]
- Huang, B.; Phelan, J.D.; Preite, S.; Gomez-Rodriguez, J.; Johansen, K.H.; Shibata, H.; Shaffer, A.L., III; Xu, Q.; Jeffrey, B.; Kirby, M.; et al. In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells. Nat. Commun. 2022, 13, 805. [Google Scholar] [CrossRef]
- Bettelli, E.; Carrier, Y.; Gao, W.; Korn, T.B.; Strom, M.; Oukka, M.; Weiner, H.L.; Kuchroo, V.K. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 2006, 441, 235–238. [Google Scholar] [CrossRef]
- Laurence, A.; Tato, C.M.; Davidson, T.S.; Kanno, Y.; Chen, Z.; Yao, Z.; Blank, R.B.; Meylan, F.; Siegel, R.; Hennighausen, L.; et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007, 26, 371–381. [Google Scholar] [CrossRef]
- Xu, H.; Wu, L.; Nguyen, H.H.; Mesa, K.R.; Raghavan, V.; Episkopou, V.; Littman, D.R. Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. J. Exp. Med. 2021, 218, e20210777. [Google Scholar] [CrossRef]
- Gerriets, V.A.; Kishton, R.J.; Johnson, M.O.; Cohen, S.; Siska, P.J.; Nichols, a.G.; Warmoes, M.O.; de Cubas, A.A.; Maciver, N.J.; Locasale, J.W.; et al. Foxp3 and Toll-like receptor signalling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 2016, 17, 1459–1466. [Google Scholar] [CrossRef]
- Howie, D.; Cobbold, S.P.; Adams, E.; Bokum, A.T.; Necula, A.S.; Zhang, W.; Huang, H.; Roberts, D.J.; Thomas, B.; Hester, S.S.; et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight 2017, 2, e89160. [Google Scholar] [CrossRef]
- Angelin, A.; Gil-de-Gómez, L.; Dahiya, S.; Jiao, J.; Guo, L.; Levine, M.H.; Wang, Z.; Quinn, W.J., 3rd; Kopinski, P.K.; Wang, L.; et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017, 25, 1282–1293.e7. [Google Scholar] [CrossRef]
- Priyadharshini, B.; Loschi, M.; Newton, R.H.; Zhang, J.W.; Finn, K.K.; Gerriets, V.A.; Huynh, A.; Rathmell, J.C.; Blazar, B.R.; Turka, L.A. Cutting edge: TGF-β and phosphatidylinositol 3-kinase signals modulate distinct metabolism of regulatory T cell subsets. J. Immunol. 2018, 201, 2215–2219. [Google Scholar] [CrossRef]
- Zeng, H.; Yang, K.; Cloer, C.; Neale, G.; Vogel, P.; Chi, H. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 2013, 499, 485–490. [Google Scholar] [CrossRef]
- Shi, H.; Chapman, N.M.; Wen, J.; Guy, C.; Long, L.; Dhungana, Y.; Rankin, S.; Pelletier, S.; Vogel, P.; Wang, H.; et al. Amino acids license kinase mTORC1 activity and Treg cell function via small G proteins Rag and Rheb. Immunity 2019, 51, 1012–1027.e7. [Google Scholar] [CrossRef]
- Pacella, I.; Procaccini, C.; Focaccetti, C.; Miacci, S.; Timperi, E.; Faicchia, D.; Severa, M.; Rizzo, F.; Coccia, E.M.; Bonacina, F.; et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl. Acad. Sci. USA 2018, 115, E6546–E6555. [Google Scholar] [CrossRef]
- Tamiya, T.; Ichiyama, K.; Kotani, H.; Fukaya, T.; Sekiya, T.; Shichita, T.; Honma, K.; Yui, K.; Matsuyama, T.; Nakao, T.; et al. Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. J. Immunol. 2013, 191, 2360–2371. [Google Scholar] [CrossRef]
- Dimeloe, S.; Gubser, P.; Loeliger, J.; Frick, C.; Develioglu, L.; Fischer, M.; Marquardsen, F.; Bantug, G.R.; Thommen, D.; Lecoultre, Y.; et al. Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. Sci. Signal. 2019, 12, eaav3334. [Google Scholar] [CrossRef] [PubMed]
- Gergely, P.; Niland, B.; Gonchoroff, N.; Pullmann, R.; Phillips, P.E.; Parl, A. Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinisation characterize altered IL-10 signaling in patients with systemic lupus erythematosus. J. Immunol. 2002, 169, 1092–1101. [Google Scholar] [CrossRef] [PubMed]
- Thomas, D.A.; Massagué, J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005, 8, 369–380. [Google Scholar] [CrossRef] [PubMed]
- Zhang, N.; Bevan, M.J. TGF-β signalling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat. Immunol. 2012, 13, 667–673. [Google Scholar] [CrossRef]
- Brownlie, R.J.; Garcia, C.; Ravasz, M.; Zehn, D.; Salmond, R.J.; Zamoyska, R. Resistance to TGFβ suppression and improved anti-tumor responses in CD8+ T cells lacking PTPN22. Nat. Commun. 2017, 8, 1343. [Google Scholar] [CrossRef]
- Pietenpol, J.A.; Holt, J.T.; Stein, R.W.; Moses, H.L. Transforming growth factor beta 1 suppression of c-myc gene transcription: Role in inhibition of keratinocyte proliferation. Proc. Natl. Acad. Sci. USA 1990, 87, 3758–3762. [Google Scholar] [CrossRef]
- Chen, C.R.; Kang, Y.; Siegel, P.M.; Massagué, J. E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression. Cell 2002, 110, 19–32. [Google Scholar] [CrossRef]
- Nguyen, T.P.; Sieg, S.F. TGF-β inhibits IL-7-induced proliferation in memory but not naïve human CD4+ T cells. J. Leukoc. Biol. 2017, 102, 499–506. [Google Scholar] [CrossRef]
- Hope, H.C.; Pickersgill, G.; Ginefra, P.; Vannini, N.; Cook, G.P.; Salmond, R.J. TGFβ limits Myc-dependent TCR-induced metabolic reprogramming in CD8+ T cells. Front. Immunol. 2022, 13, 913184. [Google Scholar] [CrossRef]
- Viel, S.; Marcais, A.; Guimaraes, F.S.; Loftus, R.; Rabilloud, J.; Grau, M.; Degouve, S.; Dejebali, S.; Sanlaville, A.; Charrier, E.; et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 2016, 9, ra19. [Google Scholar] [CrossRef]
- Gabriel, S.S.; Tsui, C.; Chisanga, D.; Weber, F.; Llano-León, M.; Gubser, P.M.; Bartholin, L.; Souza-Fonseca-Guimaraes, F.; Huntington, N.D.; Shi, W.; et al. Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity 2021, 54, 1698–1714. [Google Scholar] [CrossRef]
- Kallies, A.; Zehn, D.; Utzschneider, D.T. Precursor exhausted T cells: Key to successful immunotherapy? Nat. Rev. Immunol. 2020, 20, 128–136. [Google Scholar] [CrossRef]
- Hu, Y.; Hudson, W.H.; Kissick, H.T.; Medina, C.B.; Baptista, A.P.; Ma, C.; Liao, W.; Germain, R.N.; Turley, S.J.; Zhang, N.; et al. TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection. J. Exp. Med. 2022, 219, e20211574. [Google Scholar] [CrossRef]
- Saadey, A.A.; Yousif, A.; Osborne, N.; Shahinfar, R.; Chen, Y.L.; Laster, B.; Rajeev, M.; Bauman, P.; Webb, A.; Ghoneim, H.E. Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy. Nat. Immunol. 2023, 24, 280–294. [Google Scholar] [CrossRef]
- Araki, K.; Turner, A.P.; Shaffer, O.; Gangappa, S.; Keller, S.A.; Bachmann, M.F.; Larsen, C.P.; Ahmed, R. mTOR regulates memory CD8 T-cell differentiation. Nature 2009, 460, 108–112. [Google Scholar] [CrossRef]
- van der Windt, G.J.W.; O’Sullivan, D.; Everts, B.; Huang, S.C.C.; Buck, M.D.; Curtis, J.D.; Chang, C.H.; Smith, A.M.; Ai, T.; Faubert, B.; et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl. Acad. Sci. USA 2013, 110, 14336–14341. [Google Scholar] [CrossRef]
- Gubser, P.M.; Bantug, G.R.; Razik, L.; Fischer, M.; Dimeloe, S.; Hoenger, G.; Durovic, B.; Jauch, A.; Hess, C. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 2013, 14, 1064–1072. [Google Scholar] [CrossRef]
- O’Sullivan, D. The metabolic spectrum of memory T cells. Immunol. Cell Biol. 2019, 97, 636–646. [Google Scholar] [CrossRef]
- Corrado, M.; Pearce, E.L. Targeting memory T cell metabolism to improve immunity. J. Clin. Investig. 2022, 131, e148546. [Google Scholar] [CrossRef]
- Sanjabi, S.; Masaheb, M.M.; Flavell, R.A. Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 2009, 31, 131–144. [Google Scholar] [CrossRef] [PubMed]
- Tinoco, R.; Alcalde, V.; Yang, Y.; Sauer, K.; Zuniga, E.L. Cell-intrinsic transforming growth factor-beta signalling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 2009, 31, 145–157. [Google Scholar] [CrossRef] [PubMed]
- Ma, C.; Zhang, N. Transforming growth factor-β signalling is constantly shaping memory T-cell population. Proc. Natl. Acad. Sci. USA 2015, 112, 11013–11017. [Google Scholar] [CrossRef] [PubMed]
- Clark, R.A. Resident memory T cells in human health and disease. Sci. Transl. Med. 2015, 7, 269rv1. [Google Scholar] [CrossRef] [PubMed]
- Mackay, L.K.; Rahimpour, A.; Ma, J.Z.; Collins, N.; Stock, A.T.; Hafon, M.L.; Vega-Ramos, J.; Lauzurica, P.; Mueller, S.N.; Stefanovic, T.; et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 2013, 14, 1294–1301. [Google Scholar] [CrossRef]
- Mokrani, M.; Klibi, J.; Bluteau, D.; Bismuth, G.; Mami-Chouaib, F. Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes. J. Immunol. 2014, 192, 2471–2479. [Google Scholar] [CrossRef]
- Qiu, Z.; Chu, T.H.; Sheridan, B.S. TGF-β: Many paths to CD103+ CD8 T cell residency. Cells 2021, 10, 989. [Google Scholar] [CrossRef]
- Ferreira, C.; Barros, L.; Baptista, M.; Blankenhaus, B.; Barros, A.; Figueiredo-Campos, P.; Konjar, S.; Lainé, A.; Kamenjarin, N.; Stojanovic, A.; et al. Type 1 Treg cells promotes the generation of CD8+ tissue-resident memory T cells. Nat. Immunol. 2020, 21, 766–776. [Google Scholar] [CrossRef]
- Hasan, F.; Chiu, Y.; Shaw, R.M.; Wang, J.; Yee, C. Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program. JCI Insight 2021, 6, e138970. [Google Scholar] [CrossRef]
- Pan, Y.; Tian, T.; Park, C.O.; Lofftus, S.Y.; Mei, S.; Liu, X.; Luo, C.; O’Malley, J.T.; Gehad, A.; Teague, J.E.; et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 2017, 543, 252–256. [Google Scholar] [CrossRef]
- Liu, H.; Chen, Y.G. The interplay between TGF-β signalling and cell metabolism. Front. Cell Dev. Biol. 2022, 10, 846723. [Google Scholar] [CrossRef]
- Mastelic-Gavillet, B.; Rodrigo, B.N.; Décombaz, L.; Wang, H.; Ercolano, G.; Ahmed, R.l.; Lozano, L.E.; Ianaro, A.; Derré, L.; Valerio, M.; et al. Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells. J. Immunother. Cancer 2019, 7, 257. [Google Scholar] [CrossRef]
- Chatterjee, S.; Thyagarajan, K.; Kesarwani, P.; Song, J.H.; Soloshchenko, M.; Fu, J.; Bailey, S.R.; Vasu, C.; Kraft, A.S.; Paulos, C.M.; et al. Reducing CD73 expression by IL-1β-programmed Th17 cells improves immunotherapeutic control of tumors. Cancer Res. 2014, 74, 6048–6059. [Google Scholar] [CrossRef]
- Maj, T.; Wang, W.; Crespo, J.; Zhang, H.; Wang, W.; Wei, S.; Zhao, L.; Vatan, L.; Shao, I.; Szeliga, W.; et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 2017, 18, 1332–1341. [Google Scholar] [CrossRef]
- Chen, S.; Fan, J.; Zhang, M.; Qin, L.; Dominguez, D.; Long, A.; Wang, G.; Ma, R.; Li, H.; Zhang, Y.; et al. CD73 expression on effector T cells sustained by TGFβ facilitates tumor resistance to anti-4-1BB/CD137 therapy. Nat. Commun. 2019, 10, 150. [Google Scholar] [CrossRef]
- Beavis, P.A.; Henderson, M.A.; Giuffrida, L.; Mills, J.K.; Sek, K.; Cross, R.S.; Davenport, A.J.; John, L.B.; Mardiana, S.; Slaney, C.Y.; et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Investig. 2017, 127, 929–941. [Google Scholar] [CrossRef]
- Masoumi, E.; Jafarzadeh, L.; Mirzaei, H.R.; Alishah, K.; Fallah-Mehrjardi, K.; Rostamian, H.; Khakpoor-Koosheh, M.; Meshkani, R.; Noorbakhsh, F.; Hadjati, J. Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells. J. Exp. Clin. Cancer Res. 2020, 39, 49. [Google Scholar] [CrossRef]
- Li, N.; Tang, N.; Cheng, C.; Hu, T.; Wei, X.; Han, W.; Wang, H. Improving the anti-solid tumor efficacy of CAR-T cells by inhibiting adenosine signaling pathway. Oncoimmunology 2020, 9, 1824643. [Google Scholar] [CrossRef]
- Giuffrida, L.; Sek, K.; Henderson, M.A.; Lai, J.; Chen, A.X.Y.; Meyran, D.; Todd, K.L.; Petley, E.V.l.; Mardiana, S.; Mølck, C.; et al. CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nat. Commun. 2021, 12, 3236. [Google Scholar] [CrossRef]
- Slaats, J.; Wagena, E.; Smits, D.; Berends, A.A.; Peters, E.; Bakker, G.J.; van Erp, M.; Weigelin, B.; Adema, G.J.; Friedl, P. Adenosine A2a receptor antagonism restores additive cytotoxicity by cytotoxic T cells in metabolically perturbed tumors. Cancer Immunol. Res. 2022, 10, 1462–1474. [Google Scholar] [CrossRef]
- Seifert, M.; Benmebarek, M.R.; Briukhovestka, D.; Märkl, F.; Dörr, J.; Cadilha, B.L.; Jobst, J.; Stock, S.; Andreu-Sanz, D.; Lorenzini, T.; et al. Impact of the selective A2AR and A2BR dual antagonist AB928/etrumadenant on CAR T cell function. Br. J. Cancer 2022, 127, 2175–2185. [Google Scholar] [CrossRef] [PubMed]
- Tolcher, A.W.; Gordon, M.; Mahoney, K.M.; Seto, A.; Zavodovskaya, M.; Hsueh, C.H.; Zhai, S.; Tarnowski, T.; Jürgensmeier, J.M.; Stinson, S.; et al. Phase 1 first-in-human study of dalutrafusp alfa, an anti-CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors. J. Immunother. Cancer 2023, 11, e005267. [Google Scholar] [CrossRef] [PubMed]
- Stephen, T.L.; Rutkowski, M.R.l.; Allegrezza, M.J.; Perales-Puchalt, A.; Tesone, A.J.; Svoronos, N.; Nguyen, J.M.; Sarmin, F.; Borowsky, M.E.; Tchou, J.; et al. Transforming growth factor β-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression. Immunity 2014, 41, 427–439. [Google Scholar] [CrossRef] [PubMed]
- De Silva, P.; Garaud, S.; Solinas, C.; de Wind, A.; Van den Eyden, G.; Jose, V.; Gu-Trantien, C.; Migliori, E.; Boisson, A.; Naveaux, C.; et al. FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer. EBioMedicine 2019, 39, 226–238. [Google Scholar] [CrossRef] [PubMed]
- Ma, E.H.; Verway, M.J.; Johnson, R.M.; Roy, D.G.; Steadman, M.; Hayes, S.; Williams, K.S.; Sheldon, R.D.; Samborska, B.; Kosinski, P.A.; et al. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 2019, 51, 856–870.e5. [Google Scholar] [CrossRef] [PubMed]
- Hong, H.S.; Mbah, N.E.; Shan, M.; Loesel, K.; Lin, L.; Sajjakulnukit, P.; Correa, L.O.; Andren, A.; Lin, J.; Hayashi, A.; et al. OXPHOS promotes apoptotic resistance and cellular persistence in Th17 cells in the periphery and tumor microenvironment. Sci. Immunol. 2022, 7, eabm8182. [Google Scholar] [CrossRef]
- Shin, B.; Benavides, G.A.; Geng, J.; Koralov, S.B.; Hu, H.; Darley-Usmar, V.M.; Harrington, L.E. Mitochondrial oxidative phosphorylation regulates the fate decision between pathogenic Th17 and regulatory T cells. Cell Rep. 2020, 30, 1898–1909.e4. [Google Scholar] [CrossRef]
- Arguello, R.J.; Combes, A.J.; Char, R.; Gigan, J.P.; Baaziz, A.I.; Bousiquot, E.; Camosseto, V.; Samad, B.; Tsui, J.; Yan, P.; et al. SCENITH: A flow cytometry-based method to functionally profile energy metabolism with single-cell resolution. Cell Metab. 2020, 32, 1063–1075.e7. [Google Scholar] [CrossRef]
- Pelgrom, L.; Davis, G.; O’Shoughnessy, S.; Van Kasteren, S.; Finlay, D.; Sinclair, L. QUAS-R: Glutamine (Q) uptake assay with single cell resolution reveals metabolic heterogeneity with immune populations. bioRxiv 2022. [Google Scholar] [CrossRef]
- Bai, X.; Yi, M.; Jiao, Y.; Chu, Q.; Wu, K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. Onco Targets Ther. 2019, 12, 9257–9538. [Google Scholar] [CrossRef]
- Redman, J.M.; Friedman, J.; Robbins, Y.; Sievers, C.; Yang, X.; Lassoued, W.; Sinkoe, A.; Papanicolau-Sengos, A.; Lee, C.C.; Marte, J.L.; et al. Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer. J. Clin. Investig. 2022, 132, e161400. [Google Scholar] [CrossRef]
- Stüber, T.; Monjezi, R.; Wallstabe, L.; Kühnemundt, J.; Nietzer, S.L.; Dandekar, G.; Wöckel, A.; Einsele, H.; Wischhusen, J.; Hudecek, M. Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer. J. Immunother. Cancer 2020, 8, e000676. [Google Scholar] [CrossRef]
- Tang, N.; Cheng, C.; Zhang, X.; Qiao, M.; Li, N.; Mu, W.; Wei, X.F.; Han, W.; Wang, H. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight 2020, 5, e133977. [Google Scholar] [CrossRef]
- Narayan, V.; Barber-Rotenberg, J.S.; Jung, I.Y.; Lacey, S.F.; Rech, A.J.; Davis, M.M.; Hwang, W.T.; Lal, P.; Carpenter, E.L.; Maude, S.L.; et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase 1 trial. Nat. Med. 2022, 28, 724–734. [Google Scholar] [CrossRef]
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Salmond, R.J. Regulation of T Cell Activation and Metabolism by Transforming Growth Factor-Beta. Biology 2023, 12, 297. https://doi.org/10.3390/biology12020297
Salmond RJ. Regulation of T Cell Activation and Metabolism by Transforming Growth Factor-Beta. Biology. 2023; 12(2):297. https://doi.org/10.3390/biology12020297
Chicago/Turabian StyleSalmond, Robert J. 2023. "Regulation of T Cell Activation and Metabolism by Transforming Growth Factor-Beta" Biology 12, no. 2: 297. https://doi.org/10.3390/biology12020297
APA StyleSalmond, R. J. (2023). Regulation of T Cell Activation and Metabolism by Transforming Growth Factor-Beta. Biology, 12(2), 297. https://doi.org/10.3390/biology12020297