Abstract
The two-signal model of T cell activation states that antigen recognition by TCR provides a tolerogenic signal (termed Signal 1) unless the T cell receives simultaneous costimulation (Signal 2) that permits antigen recognition to prime activation. Our efforts to characterize genetic and biochemical factors resulting from Signal 1 alone have identified signaling molecules, transcription factors, and an epigenetic regulator that each contribute to the anergic phenotype observed. However, our most striking finding is that the same factors identified using anergy to model T cell activation versus tolerance also participate in determining the outcome of the effector phenotype of fully activated T cells. We summarize our own findings and other recent advances in the genetic and biochemical understanding of T cell activation, tolerance, and plasticity in this review.
Similar content being viewed by others
References
Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–80.
Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991;147:2461–6.
Jenkins MK. The role of cell division in the induction of clonal anergy. Immunol Today. 1992;13:69–73.
Powell JD, Lerner CG, Schwartz RH. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol. 1999;162:2775–84.
Allen A, Zheng Y, Gardner L, Safford M, Horton MR, Powell JD. The novel cyclophilin binding compound, sanglifehrin A, disassociates G1 cell cycle arrest from tolerance induction. J Immunol. 2004;172:4797–803.
Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002;109:719–31.
Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA. 2002;99:11790–5.
Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, et al. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci USA. 2002;99:11796–801.
Kowalski J, Drake C, Schwartz RH, Powell J. Non-parametric, hypothesis-based analysis of microarrays for comparison of several phenotypes. Bioinformatics. 2004;20:364–73.
Safford M, Collins S, Lutz MA, Allen A, Huang CT, Kowalski J, et al. Egr-2 and Egr-3 are negative regulators of T cell activation. Nat Immunol. 2005;6:472–80.
Mittelstadt PR, Ashwell JD. Cyclosporin A-sensitive transcription factor Egr-3 regulates Fas ligand expression. Mol Cell Biol. 1998;18:3744–51.
Mittelstadt PR, Ashwell JD. Role of Egr-2 in up-regulation of Fas ligand in normal T cells and aberrant double-negative lpr and gld T cells. J Biol Chem. 1999;274:3222–7.
Collins S, Wolfraim LA, Drake CG, Horton MR, Powell JD. Cutting edge: TCR-induced NAB2 enhances T cell function by coactivating IL-2 transcription. J Immunol. 2006;177:8301–5.
Collins S, Lutz MA, Zarek PE, Anders RA, Kersh GJ, Powell JD. Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol. 2008;38:528–36.
Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood. 2008;111:251–9.
Workman CJ, Rice DS, Dugger KJ, Kurschner C, Vignali DA. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol. 2002;32:2255–63.
Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol. 2003;33:970–9.
Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21:503–13.
Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117:3383–92.
Choi H, Cho SY, Schwartz RH, Choi K. Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell. J Immunol. 2006;176:6034–45.
Lee JS, Lee JE, Oh YM, Park JB, Choi H, Choi CY, et al. Recruitment of Sprouty1 to immune synapse regulates T cell receptor signaling. J Immunol. 2009;183:7178–86.
Gamper CJ, Agoston AT, Nelson WG, Powell JD. Identification of DNA methyltransferase 3a as a T cell receptor-induced regulator of Th1 and Th2 differentiation. J Immunol. 2009;183:2267–76.
O’Donovan KJ, Tourtellotte WG, Millbrandt J, Baraban JM. The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci. 1999;22:167–73.
Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell. 2006;126:755–66.
Sela U, Dayan M, Hershkoviz R, Lider O, Mozes E. A peptide that ameliorates lupus up-regulates the diminished expression of early growth response factors 2 and 3. J Immunol. 2008;180:1584–91.
Zhu B, Symonds AL, Martin JE, Kioussis D, Wraith DC, Li S, et al. Early growth response gene 2 (Egr-2) controls the self-tolerance of T cells and prevents the development of lupuslike autoimmune disease. J Exp Med. 2008;205:2295–307.
Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, et al. CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci USA. 2009;106:13974–9.
Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2001;414:916–20.
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103:13132–7.
Peters AH, Kubicek S, Mechtler K, O’Sullivan RJ, Derijck AA, Perez-Burgos L, et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol Cell. 2003;12:1577–89.
Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4:235–40.
Thomas RM, Gao L, Wells AD. Signals from CD28 induce stable epigenetic modification of the IL-2 promoter. J Immunol. 2005;174:4639–46.
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.
Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004;429:900–3.
Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44.
Murphy E, Shibuya K, Hosken N, Openshaw P, Maino V, Davis K, et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J Exp Med. 1996;183:901–13.
Amsen D, Spilianakis CG, Flavell RA. How are T(H)1 and T(H)2 effector cells made? Curr Opin Immunol. 2009;21:153–60.
Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107.
Shi G, Cox CA, Vistica BP, Tan C, Wawrousek EF, Gery I. Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J Immunol. 2008;181:7205–13.
Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112:362–73.
Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–67.
Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15:763–74.
Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA, Hendrich BD, et al. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002;10:81–91.
Young HA, Ghosh P, Ye J, Lederer J, Lichtman A, Gerard JR, et al. Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene. J Immunol. 1994;153:3603–10.
Acknowledgments
Christopher Gamper is supported by a Hyundai Scholar Award. Jonathan Powell is supported by ACS RSG109185 and NIH 1R01CA114227-01.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gamper, C.J., Powell, J.D. Genetic and biochemical regulation of CD4 T cell effector differentiation: insights from examination of T cell clonal anergy. Immunol Res 47, 162–171 (2010). https://doi.org/10.1007/s12026-009-8147-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12026-009-8147-0