Recent insights into the role of Akt in CD4 T-cell activation and differentiation: alternative splicing and beyond-Immunometabolism-CSCIED科技核心评价数据库-手机版

Recent insights into the role of Akt in CD4 T-cell activation and differentiation: alternative splicing and beyond

Recent insights into the role of Akt in CD4 T-cell activation and differentiation: alternative splicing and beyond

ES评分 0 浏览量：1056 下载量：0

DOI	10.1097/IN9.0000000000000015
刊名	Immunometabolism IJ
年，卷(期)	2023, 5(1)
作者	White, Tristan L. A.; Jin, Ye; Gable, Matthew J.; Morel, Penelope A.,
作者单位	[White, Tristan L. A.; Jin, Ye; Gable, Matthew J.; Morel, Penelope A.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA 15260 USA
摘要	The activation and differentiation of CD4+ T cells is a complex process that is controlled by many factors. A critical component of the signaling pathway triggered following T-cell receptor (TCR) engagement is the serine threonine kinase Akt. Akt is involved in the control of many cellular processes including proliferation, metabolism, and differentiation of specific TH-cell subsets. Recent work has shown that, depending on the nature or strength of the TCR activation, Akt may activate different sets of substrates which then lead to differential cellular outcomes. Akt plays an important role in controlling the strength of the TCR signal and several recent studies have identified novel mechanisms including control of the expression of negative regulators of TCR signaling, and the influence on regulatory T cells (Treg) and TH17 differentiation. Many of these functions are mediated via control of the FoxO family of transcription factors, that play an important role in metabolism and Th cell differentiation. A theme that is emerging is that Akt does not function in the same way in all T-cell types. We highlight differences between CD4 and CD8 T cells as well as between Treg, TH17, and TFH cells. While Akt activity has been implicated in the control of alternative splicing in tumor cells, recent studies are emerging that indicate that similar functions may exist in CD4 T cells. In this mini review, we highlight some of the recent advances in these areas of Akt function that demonstrate the varied role that Akt plays in the function of CD4 T cells.
Abstract	The activation and differentiation of CD4+ T cells is a complex process that is controlled by many factors. A critical component of the signaling pathway triggered following T-cell receptor (TCR) engagement is the serine threonine kinase Akt. Akt is involved in the control of many cellular processes including proliferation, metabolism, and differentiation of specific TH-cell subsets. Recent work has shown that, depending on the nature or strength of the TCR activation, Akt may activate different sets of substrates which then lead to differential cellular outcomes. Akt plays an important role in controlling the strength of the TCR signal and several recent studies have identified novel mechanisms including control of the expression of negative regulators of TCR signaling, and the influence on regulatory T cells (Treg) and TH17 differentiation. Many of these functions are mediated via control of the FoxO family of transcription factors, that play an important role in metabolism and Th cell differentiation. A theme that is emerging is that Akt does not function in the same way in all T-cell types. We highlight differences between CD4 and CD8 T cells as well as between Treg, TH17, and TFH cells. While Akt activity has been implicated in the control of alternative splicing in tumor cells, recent studies are emerging that indicate that similar functions may exist in CD4 T cells. In this mini review, we highlight some of the recent advances in these areas of Akt function that demonstrate the varied role that Akt plays in the function of CD4 T cells.
关键词	T helper cell; Akt; differentiation; alternative splicing; signaling
KeyWord	T helper cell; Akt; differentiation; alternative splicing; signaling
基金项目
页码	1-4

参考文献
相关文献

[1]. DuPage M, Bluestone JA. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol. 2016;16:149–63. doi: 10.1038/nri.2015.18.

[2]. Morel PA. Differential T-cell receptor signals for T helper cell programming. Immunology. 2018;155:63–71. doi: 10.1111/imm.12945.

[3]. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89. doi: 10.1146/annurev-immunol-030409-101212.

[4]. Finlay D, Cantrell D. The coordination of T-cell function by serine/threonine kinases. Cold Spring Harb Perspect Biol. 2011;3:a002261. doi: 10.1101/cshperspect.a002261.

[5]. Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44. doi: 10.1016/j.immuni.2009.04.014.

[6]. Delgoffe GM, Pollizzi KN, Waickman AT, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303. doi: 10.1038/ni.2005.

[7]. Park Y, Jin HS, Lopez J, et al. TSC1 regulates the balance between effector and regulatory T cells. J Clin Invest. 2013;123:5165–78. doi: 10.1172/JCI69751.

[8]. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997;7:261–9. doi: 10.1016/s0960-9822(06)00122-9.

[9]. Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101. doi: 10.1126/science.1106148.

[10]. Waugh C, Sinclair L, Finlay D, et al. Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Mol Cell Biol. 2009;29:5952–62. doi: 10.1128/MCB.00585-09.

[11]. Hawse WF, Cattley RT. T cells transduce T-cell receptor signal strength by generating different phosphatidylinositols. J Biol Chem. 2019;294:4793–805. doi: 10.1074/jbc.RA118.006524.

[12]. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med. 2008;205:565–74. doi: 10.1084/jem.20071477.

[13]. Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA. 2008;105:7797–802. doi: 10.1073/pnas.0800928105.

[14]. Turner MS, Kane LP, Morel PA. Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion. J Immunol. 2009;183:4895–903. doi: 10.4049/jimmunol.0901459.

[15]. Hawse WF, Boggess WC, Morel PA. TCR signal strength regulates Akt substrate specificity to induce alternate murine Th and T regulatory cell differentiation programs. J Immunol. 2017;199:589–97. doi: 10.4049/jimmunol.1700369.

[16]. Hawse WF, Sheehan RP, Miskov-Zivanov N, et al. Cutting edge: differential regulation of PTEN by TCR, Akt, and FoxO1 controls CD4+ T cell fate decisions. J Immunol. 2015;194:4615–9. doi: 10.4049/jimmunol.1402554.

[17]. Cai W, Zhang J, Zhou H, et al. Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity. Genes Dis. 2022;9:562–75. doi: 10.1016/j.gendis.2021.07.005.

[18]. Mercadante ER, Lorenz UM. T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells. J Immunol. 2017;199:129–37. doi: 10.4049/jimmunol.1602171. doi: 10.4049/jimmunol.1602171.

[19]. Tran CW, Saibil SD, Le Bihan T, et al. Glycogen synthase Kinase-3 modulates Cbl-b and constrains T cell activation. J Immunol. 2017;199:4056–65. doi: 10.4049/jimmunol.1600396.

[20]. Fanelli G, Romano M, Nova-Lamperti E, et al. PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLoS Biol. 2021;19:e3001199. doi: 10.1371/journal.pbio.3001199.

[21]. Miyakoda M, Honma K, Kimura D, et al. Differential requirements for IRF4 in the clonal expansion and homeostatic proliferation of naive and memory murine CD8(+) T cells. Eur J Immunol. 2018;48:1319–28. doi: 10.1002/eji.201747120.

[22]. Kotzin JJ, Iseka F, Wright J, et al. The long noncoding RNA Morrbid regulates CD8 T cells in response to viral infection. Proc Natl Acad Sci USA. 2019;116:11916–25. doi: 10.1073/pnas.1819457116.

[23]. Spinelli L, Marchingo JM, Nomura A, et al. Phosphoinositide 3-Kinase p110 delta differentially restrains and directs naive versus effector CD8(+) T cell transcriptional programs. Front Immunol. 2021;12:691997. doi: 10.3389/fimmu.2021.691997.

[24]. Revu S, Wu J, Henkel M, et al. IL-23 and IL-1beta drive human TH17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation. Cell Rep. 2018;22:2642–53. doi: 10.1016/j.celrep.2018.02.044.

[25]. Krummey SM, Hartigan CR, Liu D, et al. CD28-dependent CTLA-4 expression fine-tunes the activation of human TH17 cells. iScience. 2020;23:100912.

[26]. Chapman NM, Shrestha S, Chi H. Metabolism in immune cell differentiation and function. Adv Exp Med Biol. 2017;1011:1–85. doi: 10.1007/978-94-024-1170-6_1.

[27]. Hawse WF, Cattley RT, Wendell SG. Cutting edge: TCR signal strength regulates Acetyl-CoA metabolism via AKT. J Immunol. 2019;203:2771–5. doi: 10.4049/jimmunol.1900749.

[28]. Jones N, Vincent EE, Cronin JG, et al. Akt and STAT5 mediate naive human CD4+ T-cell early metabolic response to TCR stimulation. Nat Commun. 2019;10:2042. doi: 10.1038/s41467-019-10023-4.

[29]. Menk AV, Scharping NE, Moreci RS, et al. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 2018;22:1509–21. doi: 10.1016/j.celrep.2018.01.040.

[30]. Ouyang W, Beckett O, Ma Q, et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol. 2010;11:618–27. doi: 10.1038/ni.1884.

[31]. Ouyang W, Liao W, Luo CT, et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. 2012;491:554–9. doi: 10.1038/nature11581.

[32]. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68. doi: 10.1016/s0092-8674(00)80595-4.

[33]. Lam AJ, Haque M, Ward-Hartstonge KA, et al. PTEN is required for human Treg suppression of costimulation in vitro. Eur J Immunol. 2022;52(9):1482–97. doi: 10.1002/eji.202249888.

[34]. Schall D, Schmitt F, Reis B, et al. SLy1 regulates T-cell proliferation during Listeria monocytogenes infection in a Foxo1-dependent manner. Eur J Immunol. 2015;45:3087–97. doi: 10.1002/eji.201545609.

[35]. Marcel N, Hedrick SM. A key control point in the T cell response to chronic infection and neoplasia: FOXO1. Curr Opin Immunol. 2020;63:51–60. doi: 10.1016/j.coi.2020.02.001.

[36]. Xing YQ, Li A, Yang Y, et al. The regulation of FOXO1 and its role in disease progression. Life Sci. 2018;193:124–31. doi: 10.1016/j.lfs.2017.11.030.

[37]. Stone EL, Pepper M, Katayama CD, et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote TFH cell differentiation. Immunity. 2015;42:239–51. doi: 10.1016/j.immuni.2015.01.017.

[38]. Gray SM, Kaech SM, Staron MM. The interface between transcriptional and epigenetic control of effector and memory CD8(+) T-cell differentiation. Immunol Rev. 2014;261:157–68. doi: 10.1111/imr.12205.

[39]. Xu A, Leary SC, Islam MF, et al. Prosurvival IL-7-stimulated weak strength of mTORC1-S6K controls T cell memory via transcriptional FOXO1-TCF1-Id3 and metabolic AMPKalpha1-ULK1-ATG7 pathways. J Immunol. 2022;208:155–68. doi: 10.4049/jimmunol.2100452.

[40]. Gigoux M, Shang J, Pak Y, et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc Natl Acad Sci USA. 2009;106:20371–6. doi: 10.1073/pnas.0911573106.

[41]. Xiao N, Eto D, Elly C, et al. The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol. 2014;15:657–66. doi: 10.1038/ni.2912.

[42]. Harada Y, Harada Y, Elly C, et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. 2010;207:1381–91. doi: 10.1084/jem.20100004.

[43]. Kerdiles YM, Stone EL, Beisner DR, et al. Foxo transcription factors control regulatory T cell development and function. Immunity. 2010;33:890–904. doi: 10.1016/j.immuni.2010.12.002.

[44]. Newton RH, Shrestha S, Sullivan JM, et al. Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol. 2018;19:838–48. doi: 10.1038/s41590-018-0157-4.

[45]. Jean-Philippe J, Paz S, Caputi M. hnRNP A1: the Swiss army knife of gene expression. Int J Mol Sci. 2013;14:18999–9024. doi: 10.3390/ijms140918999.

[46]. Jo OD, Martin J, Bernath A, et al. Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. J Biol Chem. 2008;283:23274–87. doi: 10.1074/jbc.M801185200.

[47]. Blake D, Lynch KW. The three as: alternative splicing, alternative polyadenylation and their impact on apoptosis in immune function. Immunol Rev. 2021;304:30–50. doi: 10.1111/imr.13018.

[48]. Fu XD AM Jr. Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet. 2014;15:689. doi: 10.1038/nrg3778.

[49]. Ozay EI, Shanthalingam S, Torres JA, et al. Protein kinase C theta modulates PCMT1 through hnRNPL to regulate FOXP3 stability in regulatory T cells. Mol Ther. 2020;28:2220–36. doi: 10.1016/j.ymthe.2020.06.012.

[50]. Sanidas I, Polytarchou C, Hatziapostolou M, et al. Phosphoproteomics screen reveals akt isoform-specific signals linking RNA processing to lung cancer. Mol Cell. 2014;53:577–90. doi: 10.1016/j.molcel.2013.12.018.

[51]. Shultz JC, Goehe RW, Wijesinghe DS, et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3-kinase/Akt pathway via phosphorylation of SRp30a. Cancer Res. 2010;70:9185–96. doi: 10.1158/0008-5472.CAN-10-1545.

[52]. Vu NT, Park MA, Shultz JC, et al. hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L. J Biol Chem. 2013;288:8575–84. doi: 10.1074/jbc.M112.443333.

[53]. Cheng L, Tang X, Xu L, et al. Interferon-gamma upregulates Delta42PD1 expression on human monocytes via the PI3K/AKT pathway. Immunobiology. 2019;224:388–96. doi: 10.1016/j.imbio.2019.02.009.

[54]. Lau CI, Rowell J, Yanez DC, et al. The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection. Development. 2021;148:dev199754. doi: 10.1242/dev.199754.

[55]. Liu X, Tian N, Huang Q, et al. hnRNPA1 enhances FOXP3 stability to promote the differentiation and functions of regulatory T cells. FEBS Lett. 2021;595:1962–74. doi: 10.1002/1873-3468.14142.

[56]. Preussner M, Schreiner S, Hung LH, et al. HnRNP L and L-like cooperate in multiple-exon regulation of CD45 alternative splicing. Nucleic Acids Res. 2012;40:5666–78. doi: 10.1093/nar/gks221.

[57]. Gaudreau MC, Heyd F, Bastien R, et al. Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L regulates development, proliferation, and migration of thymic pre-T cells. J Immunol. 2012;188:5377–88. doi: 10.4049/jimmunol.1103142.

[58]. Mir Q, Lakshmipati DK, Ulrich BJ, et al. Comparative analysis of alternative splicing profiles in Th cell subsets reveals extensive cell type-specific effects modulated by a network of transcription factors and RNA-Binding proteins. Immunohorizons. 2021;5:760–71. doi: 10.4049/immunohorizons.2100060.

引用本文

White, Tristan L. A.; Jin, Ye; Gable, Matthew J.; Morel, Penelope A.. Recent insights into the role of Akt in CD4 T-cell activation and differentiation: alternative splicing and beyond [J]. Immunometabolism. 2023; 5; (1). 1 - 4.

文献评论

相关学者

相关机构