The CD4/CD8 Lineages: Central Decisions and Peripheral Modifications for T Lymphocytes

  • Hirokazu Tanaka
  • Ichiro TaniuchiEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 373)


CD4+ helper and CD8+ cytotoxic T cells, two major subsets of αβTCR expressing lymphocytes, are differentiated from common precursor CD4+CD8+ double-positive (DP) thymocytes. Bifurcation of the CD4+/CD8+ lineages in the thymus is a multilayered process and is thought to culminate in a loss of developmental plasticity between these functional subsets. Advances in the last decade have deepened our understanding of the transcription control mechanisms governing CD4 versus CD8 lineage commitment. Reciprocal expression and antagonistic interplay between two transcription factors, ThPOK and Runx3, is crucial for driving thymocyte decisions between these two cell fates. Here, we first focus on the regulation of ThPOK expression and its role in directing helper T cell development. We then discuss a novel aspect of the ThPOK/Runx3 axis in modifying CD4+ T cell function upon exposure to gut microenvironment.


Runx3 Expression Distal Regulatory Element Thymocyte Differentiation Runx Binding Runx3 Gene Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from Grant-in-Aid for Scientific Research (S) and for Scientific Research on Priority Areas (I.T.). We are grateful to Dr. Hilde Cheroutre, Dr. Wooseok Seo, and Dr. Eugene Oltz for critically reading the manuscript and providing valuable advice.


  1. Albu DI, Feng D, Bhattacharya D, Jenkins NA, Copeland NG, Liu P, Avram D (2007) BCL11B is required for positive selection and survival of double-positive thymocytes. J Exp Med 204:3003–3015PubMedCrossRefGoogle Scholar
  2. Aliahmad P, Kaye J (2008) Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med 205:245–256PubMedCrossRefGoogle Scholar
  3. Aliahmad P, Kadavallore A, de la Torre B, Kappes D, Kaye J (2011) TOX is required for development of the CD4 T cell lineage gene program. J Immunol 187:5931–5940 Google Scholar
  4. Alvarez JD, Yasui DH, Niida H, Joh T, Loh DY, Kohwi-Shigematsu T (2000) The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development. Genes Dev 14:521–535PubMedGoogle Scholar
  5. Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, Easterbrook P, Grey P, Smith D, McMichael AJ, Cooper DA, Rowland-Jones SL, Kelleher AD (2002) Characterization of CD4+ CTLs ex vivo. J Immunol 168:5954–5958PubMedGoogle Scholar
  6. Bilic I, Koesters C, Unger B, Sekimata M, Hertweck A, Maschek R, Wilson CB, Ellmeier W (2006) Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nat Immunol 7:392–400PubMedCrossRefGoogle Scholar
  7. Brown DM (2010) Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy. Cell Immunol 262:89–95PubMedCrossRefGoogle Scholar
  8. Brugnera E, Bhandoola A, Cibotti R, Yu Q, Guinter TI, Yamashita Y, Sharrow SO, Singer A (2000) Coreceptor reversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 13:59–71PubMedCrossRefGoogle Scholar
  9. Carpenter AC, Bosselut R (2010) Decision checkpoints in the thymus. Nat Immunol 11:666–673PubMedCrossRefGoogle Scholar
  10. Carpenter AC, Grainger JR, Xiong Y, Kanno Y, Chu HH, Wang L, Naik S, Dos Santos L, Wei L, Jenkins MK, O’Shea JJ, Belkaid Y, Bosselut R (2012) The Transcription Factors Thpok and LRF Are Necessary and Partly Redundant for T Helper Cell Differentiation. Immunity 37:622–633PubMedCrossRefGoogle Scholar
  11. Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, Groner Y, Rao A (2009) Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med 206:51–59PubMedCrossRefGoogle Scholar
  12. Dave VP, Allman D, Keefe R, Hardy RR, Kappes DJ (1998) HD mice: a novel mouse mutant with a specific defect in the generation of CD4+ T cells. Proc Natl Acad Sci U S A 95:8187–8192PubMedCrossRefGoogle Scholar
  13. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM (2007) Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol 8:145–153PubMedCrossRefGoogle Scholar
  14. Egawa T, Littman DR (2008) ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat Immunol 9:1131–1139PubMedCrossRefGoogle Scholar
  15. Egawa T, Taniuchi I (2009) Antagonistic interplay between ThPOK and Runx in lineage choice of thymocytes. Blood Cells Mol Dis 43:27–29PubMedCrossRefGoogle Scholar
  16. Egawa T, Tillman RE, Naoe Y, Taniuchi I, Littman DR (2007) The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. J Exp Med 204:1945–1957PubMedCrossRefGoogle Scholar
  17. Ellmeier W, Sunshine MJ, Losos K, Hatam F, Littman DR (1997) An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7:537–547PubMedCrossRefGoogle Scholar
  18. Ellmeier W, Sunshine MJ, Losos K, Littman DR (1998) Multiple developmental stage-specific enhancers regulate CD8 expression in developing thymocytes and in thymus-independent T cells. Immunity 9:485–496PubMedCrossRefGoogle Scholar
  19. Ellmeier W, Sawada S, Littman DR (1999) The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu Rev Immunol 17:523–554PubMedCrossRefGoogle Scholar
  20. Gascoigne NR, Palmer E (2011) Signaling in thymic selection. Curr Opin Immunol 23:207–212PubMedCrossRefGoogle Scholar
  21. Germain RN (2002) T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2:309–322PubMedCrossRefGoogle Scholar
  22. Grenningloh R, Tai TS, Frahm N, Hongo TC, Chicoine AT, Brander C, Kaufmann DE, Ho IC (2011) Ets-1 maintains IL-7 receptor expression in peripheral T cells. J Immunol 186:969–976PubMedCrossRefGoogle Scholar
  23. Grusby MJ, Johnson RS, Papaioannou VE, Glimcher LH (1991) Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science 253:1417–1420PubMedCrossRefGoogle Scholar
  24. Hassan H, Sakaguchi S, Tenno M, Kopf A, Boucheron N, Carpenter AC, Egawa T, Taniuchi I, Ellmeier W (2011) Cd8 enhancer E8I and Runx factors regulate CD8alpha expression in activated CD8+ T cells. Proc Natl Acad Sci U S A 108:18330–18335PubMedCrossRefGoogle Scholar
  25. He X, Dave VP, Zhang Y, Hua X, Nicolas E, Xu W, Roe BA, Kappes DJ (2005) The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433:826–833PubMedCrossRefGoogle Scholar
  26. He X, Park K, Wang H, He X, Zhang Y, Hua X, Li Y, Kappes DJ (2008) CD4-CD8 lineage commitment is regulated by a silencer element at the ThPOK transcription-factor locus. Immunity 28:346–358PubMedCrossRefGoogle Scholar
  27. Hedrick SM (2008) Thymus lineage commitment: a single switch. Immunity 28:297–299PubMedCrossRefGoogle Scholar
  28. Hosoya T, Maillard I, Engel JD (2010) From the cradle to the grave: activities of GATA-3 throughout T-cell development and differentiation. Immunol Rev 238:110–125PubMedCrossRefGoogle Scholar
  29. Hostert A, Garefalaki A, Mavria G, Tolaini M, Roderick K, Norton T, Mee PJ, Tybulewicz VL, Coles M, Kioussis D (1998) Hierarchical interactions of control elements determine CD8α gene expression in subsets of thymocytes and peripheral T cells. Immunity 9:497–508PubMedCrossRefGoogle Scholar
  30. Ikawa T, Hirose S, Masuda K, Kakugawa K, Satoh R, Shibano-Satoh A, Kominami R, Katsura Y, Kawamoto H (2010) An essential developmental checkpoint for production of the T cell lineage. Science 329:93–96PubMedCrossRefGoogle Scholar
  31. Jenkinson SR, Intlekofer AM, Sun G, Feigenbaum L, Reiner SL, Bosselut R (2007) Expression of the transcription factor cKrox in peripheral CD8 T cells reveals substantial postthymic plasticity in CD4-CD8 lineage differentiation. J Exp Med 204:267–272Google Scholar
  32. Jones ME, Zhuang Y (2007) Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors. Immunity 27:860–870PubMedCrossRefGoogle Scholar
  33. Jones-Mason ME, Zhao X, Kappes D, Lasorella A, Iavarone A, Zhuang Y (2012) E protein transcription factors are required for the development of CD4+ lineage T cells. Immunity 36:348–361PubMedCrossRefGoogle Scholar
  34. Kastner P, Chan S, Vogel WK, Zhang LJ, Topark-Ngarm A, Golonzhka O, Jost B, Le Gras S, Gross MK, Leid M (2010) Bcl11b represses a mature T-cell gene expression program in immature CD4+CD8+ thymocytes. Eur J Immunol 40:2143–2154PubMedCrossRefGoogle Scholar
  35. Koller BH, Marrack P, Kappler JW, Smithies O (1990) Normal development of mice deficient in beta 2 M, MHC class I proteins, and CD8+ T cells. Science 248:1227–1230PubMedCrossRefGoogle Scholar
  36. Konkel JE, Maruyama T, Carpenter AC, Xiong Y, Zamarron BF, Hall BE, Kulkarni AB, Zhang P, Bosselut R, Chen W (2011) Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat Immunol 12:312–319PubMedCrossRefGoogle Scholar
  37. Lee SU, Maeda T (2012) POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function. Immunol Rev 247:107–119PubMedCrossRefGoogle Scholar
  38. Lee SU, Maeda M, Ishikawa Y, Li SM, Wilson A, Jubb AM, Sakurai N, Weng L, Fiorini E, Radtke F, Yan M, Macdonald HR, Chen CC, Maeda T (2012) LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance. Blood 121:918–929Google Scholar
  39. Li L, Leid M, Rothenberg EV (2010a) An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329:89–93PubMedCrossRefGoogle Scholar
  40. Li P, Burke S, Wang J, Chen X, Ortiz M, Lee SC, Lu D, Campos L, Goulding D, Ng BL, Dougan G, Huntly B, Gottgens B, Jenkins NA, Copeland NG, Colucci F, Liu P (2010b) Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329:85–89PubMedCrossRefGoogle Scholar
  41. Maeda T, Merghoub T, Hobbs RM, Dong L, Maeda M, Zakrzewski J, van den Brink MR, Zelent A, Shigematsu H, Akashi K, Teruya-Feldstein J, Cattoretti G, Pandolfi PP (2007) Regulation of B versus T lymphoid lineage fate decision by the proto-oncogene LRF. Science 316:860–866PubMedCrossRefGoogle Scholar
  42. Marshall NB, Swain SL (2011) Cytotoxic CD4 T cells in antiviral immunity. J Biomed Biotechnol 2011:954602PubMedCrossRefGoogle Scholar
  43. McCaughtry TM, Etzensperger R, Alag A, Tai X, Kurtulus S, Park JH, Grinberg A, Love P, Feigenbaum L, Erman B, Singer A (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209:2263–2276PubMedCrossRefGoogle Scholar
  44. Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R, Naoe Y, Reis B, Huang Y, Lambolez F, Docherty M, Attinger A, Shui JW, Kim G, Lena C, Sakaguchi S, Miyamoto C, Wang P, Atarashi K, Park Y, Nakayama T, Honda K, Ellmeier W, Kronenberg M, Taniuchi I, Cheroutre H (2013) Transcriptional reprogramming of mature CD4 T helper cells generates distinct MHC class II restricted cytotoxic T lymphocytes. Nat Immunol 14:281–289Google Scholar
  45. Muroi S, Naoe Y, Miyamoto C, Akiyama K, Ikawa T, Masuda K, Kawamoto H, Taniuchi I (2008) Cascading suppression of transcriptional silencers by ThPOK seals helper T cell fate. Nat Immunol 9:1113–1121PubMedCrossRefGoogle Scholar
  46. Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ (2012) Helper T cell diversity and plasticity. Curr Opin Immunol 24:297–302PubMedCrossRefGoogle Scholar
  47. Naoe Y, Setoguchi R, Akiyama K, Muroi S, Kuroda M, Hatam F, Littman DR, Taniuchi I (2007) Repression of interleukin-4 in T helper type 1 cells by Runx/Cbf beta binding to the Il4 silencer. J Exp Med 204:1749–1755PubMedCrossRefGoogle Scholar
  48. Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, Kimura MY, Cui Y, Lucas PJ, Gress RE, Kubo M, Hennighausen L, Feigenbaum L, Singer A (2010) Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol 11:257–264PubMedCrossRefGoogle Scholar
  49. Pobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, Park JH, Singer A (2012) Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol 13:569–578PubMedCrossRefGoogle Scholar
  50. Reis B, Rogoz A, Costa-Pinto F, Taniuchi I, Mucida D (2013) Mutual expression of Runx3 and ThPOK regulates intestinal CD4 T cell immunity. Nat Immunol 14:271–280Google Scholar
  51. Rui J, Liu H, Zhu X, Cui Y, Liu X (2012) Epigenetic silencing of CD8 genes by ThPOK-mediated deacetylation during CD4 T cell differentiation. J Immunol 189:1380–1390PubMedCrossRefGoogle Scholar
  52. Sakaguchi S, Hombauer M, Bilic I, Naoe Y, Schebesta A, Taniuchi I, Ellmeier W (2010) The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes. Nat Immunol 11:442–448PubMedCrossRefGoogle Scholar
  53. Sato T, Ohno S, Hayashi T, Sato C, Kohu K, Satake M, Habu S (2005) Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22:317–328PubMedCrossRefGoogle Scholar
  54. Setoguchi R, Tachibana M, Naoe Y, Muroi S, Akiyama K, Tezuka C, Okuda T, Taniuchi I (2008) Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science 319:822–825PubMedCrossRefGoogle Scholar
  55. Setoguchi R, Taniuchi I, Bevan MJ (2009) ThPOK derepression is required for robust CD8 T cell responses to viral infection. J Immunol 183:4467–4474PubMedCrossRefGoogle Scholar
  56. Singer A, Bosselut R (2004) CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv Immunol 83:91–131PubMedCrossRefGoogle Scholar
  57. Singer A, Adoro S, Park JH (2008) Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol 8:788–801PubMedCrossRefGoogle Scholar
  58. Singh H (2007) Shaping a helper T cell identity. Nat Immunol 8:119–120PubMedCrossRefGoogle Scholar
  59. Sun G, Liu X, Mercado P, Jenkinson SR, Kypriotou M, Feigenbaum L, Galera P, Bosselut R (2005) The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat Immunol 6:373–381PubMedCrossRefGoogle Scholar
  60. Tanaka H, Naito T, Muroi S, Seo W, Chihara R, Miyamoto C, Kominami R Taniuchi I (2013) Epigenetic Thpok silencing limits the time window to choose CD4+ helper-lineage fate in the thymus. EMBO J. 2013 Mar 12. doi: 10.1038/emboj.2013.47
  61. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T, Ito Y, Littman DR (2002) Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111:621–633PubMedCrossRefGoogle Scholar
  62. Vanvalkenburgh J, Albu DI, Bapanpally C, Casanova S, Califano D, Jones DM, Ignatowicz L, Kawamoto S, Fagarasan S, Jenkins NA, Copeland NG, Liu P, Avram D (2011) Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J Exp Med 208:2069–2081PubMedCrossRefGoogle Scholar
  63. Wang L, Wildt KF, Castro E, Xiong Y, Feigenbaum L, Tessarollo L, Bosselut R (2008a) The zinc finger transcription factor Zbtb7b represses CD8-lineage gene expression in peripheral CD4+ T cells. Immunity 29:876–887PubMedCrossRefGoogle Scholar
  64. Wang L, Wildt KF, Zhu J, Zhang X, Feigenbaum L, Tessarollo L, Paul WE, Fowlkes BJ, Bosselut R (2008b) Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells. Nat Immunol 9:1122–1130PubMedCrossRefGoogle Scholar
  65. Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X, Bushweller JH, Bories JC, Alt FW, Ryan G, Liu PP, Wynshaw-Boris A, Binder M, Marin-Padilla M, Sharpe AH, Speck NA (1996) The CBFβ subunit is essential for CBFα2 (AML1) function in vivo. Cell 87:697–708PubMedCrossRefGoogle Scholar
  66. Woolf E, Xiao C, Fainaru O, Lotem J, Rosen D, Negreanu V, Bernstein Y, Goldenberg D, Brenner O, Berke G, Levanon D, Groner Y (2003) Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc Natl Acad Sci U S A 100:7731–7736PubMedCrossRefGoogle Scholar
  67. Zamisch M, Tian L, Grenningloh R, Xiong Y, Wildt KF, Ehlers M, Ho IC, Bosselut R (2009) The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus. J Exp Med 206:2685–2699PubMedCrossRefGoogle Scholar
  68. Zhang M, Zhang J, Rui J, Liu X (2010) p300-mediated acetylation stabilizes the Th-inducing POK factor. J Immunol 185:3960–3969PubMedCrossRefGoogle Scholar
  69. Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF Jr, Guo L, Paul WE (2004) Conditional deletion of Gata3 shows its essential function in TH1–TH2 responses. Nat Immunol 5:1157–1165PubMedCrossRefGoogle Scholar
  70. Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE (2006) GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res 16:3–10PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Laboratory for Transcriptional RegulationRIKEN Research Center for Allergy and ImmunologyYokohamaJapan

Personalised recommendations