Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Book cover Thymic Development and Selection of T Lymphocytes

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 373))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 204:3003–3015

    Article  PubMed  CAS  Google Scholar 

  • Aliahmad P, Kaye J (2008) Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med 205:245–256

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 14:521–535

    PubMed  CAS  Google Scholar 

  • 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 168:5954–5958

    PubMed  CAS  Google Scholar 

  • 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 7:392–400

    Article  PubMed  CAS  Google Scholar 

  • Brown DM (2010) Cytolytic CD4 cells: Direct mediators in infectious disease and malignancy. Cell Immunol 262:89–95

    Article  PubMed  CAS  Google Scholar 

  • 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 13:59–71

    Article  PubMed  CAS  Google Scholar 

  • Carpenter AC, Bosselut R (2010) Decision checkpoints in the thymus. Nat Immunol 11:666–673

    Article  PubMed  CAS  Google Scholar 

  • 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 37:622–633

    Article  PubMed  CAS  Google Scholar 

  • 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 206:51–59

    Article  PubMed  CAS  Google Scholar 

  • 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 95:8187–8192

    Article  PubMed  CAS  Google Scholar 

  • 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 8:145–153

    Article  PubMed  CAS  Google Scholar 

  • 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 9:1131–1139

    Article  PubMed  CAS  Google Scholar 

  • Egawa T, Taniuchi I (2009) Antagonistic interplay between ThPOK and Runx in lineage choice of thymocytes. Blood Cells Mol Dis 43:27–29

    Article  PubMed  CAS  Google Scholar 

  • 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 204:1945–1957

    Article  PubMed  CAS  Google Scholar 

  • 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 7:537–547

    Article  PubMed  CAS  Google Scholar 

  • 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 9:485–496

    Article  PubMed  CAS  Google Scholar 

  • Ellmeier W, Sawada S, Littman DR (1999) The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu Rev Immunol 17:523–554

    Article  PubMed  CAS  Google Scholar 

  • Gascoigne NR, Palmer E (2011) Signaling in thymic selection. Curr Opin Immunol 23:207–212

    Article  PubMed  CAS  Google Scholar 

  • Germain RN (2002) T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2:309–322

    Article  PubMed  CAS  Google Scholar 

  • 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 186:969–976

    Article  PubMed  CAS  Google Scholar 

  • Grusby MJ, Johnson RS, Papaioannou VE, Glimcher LH (1991) Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science 253:1417–1420

    Article  PubMed  CAS  Google Scholar 

  • 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 108:18330–18335

    Article  PubMed  CAS  Google Scholar 

  • 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 433:826–833

    Article  PubMed  CAS  Google Scholar 

  • 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 28:346–358

    Article  PubMed  CAS  Google Scholar 

  • Hedrick SM (2008) Thymus lineage commitment: a single switch. Immunity 28:297–299

    Article  PubMed  CAS  Google Scholar 

  • 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 238:110–125

    Article  PubMed  CAS  Google Scholar 

  • 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 9:497–508

    Article  PubMed  CAS  Google Scholar 

  • 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 329:93–96

    Article  PubMed  CAS  Google Scholar 

  • 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 204:267–272

    Google Scholar 

  • 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 27:860–870

    Article  PubMed  CAS  Google Scholar 

  • 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 36:348–361

    Article  PubMed  CAS  Google Scholar 

  • 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 40:2143–2154

    Article  PubMed  CAS  Google Scholar 

  • 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 248:1227–1230

    Article  PubMed  CAS  Google Scholar 

  • 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 12:312–319

    Article  PubMed  CAS  Google Scholar 

  • Lee SU, Maeda T (2012) POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function. Immunol Rev 247:107–119

    Article  PubMed  Google Scholar 

  • 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 121:918–929

    Google Scholar 

  • Li L, Leid M, Rothenberg EV (2010a) An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329:89–93

    Article  PubMed  CAS  Google Scholar 

  • 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 329:85–89

    Article  PubMed  CAS  Google Scholar 

  • 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 316:860–866

    Article  PubMed  CAS  Google Scholar 

  • Marshall NB, Swain SL (2011) Cytotoxic CD4 T cells in antiviral immunity. J Biomed Biotechnol 2011:954602

    Article  PubMed  Google Scholar 

  • 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 209:2263–2276

    Article  PubMed  CAS  Google Scholar 

  • 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 14:281–289

    Google Scholar 

  • 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 9:1113–1121

    Article  PubMed  CAS  Google Scholar 

  • Nakayamada S, Takahashi H, Kanno Y, O’Shea JJ (2012) Helper T cell diversity and plasticity. Curr Opin Immunol 24:297–302

    Article  PubMed  CAS  Google Scholar 

  • 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 204:1749–1755

    Article  PubMed  CAS  Google Scholar 

  • 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 11:257–264

    Article  PubMed  CAS  Google Scholar 

  • 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 13:569–578

    Article  PubMed  CAS  Google Scholar 

  • 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 14:271–280

    Google Scholar 

  • 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 189:1380–1390

    Article  PubMed  CAS  Google Scholar 

  • 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 11:442–448

    Article  PubMed  CAS  Google Scholar 

  • 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 22:317–328

    Article  PubMed  CAS  Google Scholar 

  • 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 319:822–825

    Article  PubMed  CAS  Google Scholar 

  • Setoguchi R, Taniuchi I, Bevan MJ (2009) ThPOK derepression is required for robust CD8 T cell responses to viral infection. J Immunol 183:4467–4474

    Article  PubMed  CAS  Google Scholar 

  • Singer A, Bosselut R (2004) CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: analysis of the CD4/CD8 lineage decision. Adv Immunol 83:91–131

    Article  PubMed  CAS  Google Scholar 

  • 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 8:788–801

    Article  PubMed  CAS  Google Scholar 

  • Singh H (2007) Shaping a helper T cell identity. Nat Immunol 8:119–120

    Article  PubMed  CAS  Google Scholar 

  • 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 6:373–381

    Article  PubMed  CAS  Google Scholar 

  • 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

  • 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 111:621–633

    Article  PubMed  CAS  Google Scholar 

  • 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 208:2069–2081

    Article  PubMed  CAS  Google Scholar 

  • 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 29:876–887

    Article  PubMed  Google Scholar 

  • 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 9:1122–1130

    Article  PubMed  CAS  Google Scholar 

  • 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 87:697–708

    Article  PubMed  CAS  Google Scholar 

  • 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 100:7731–7736

    Article  PubMed  CAS  Google Scholar 

  • 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 206:2685–2699

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Zhang J, Rui J, Liu X (2010) p300-mediated acetylation stabilizes the Th-inducing POK factor. J Immunol 185:3960–3969

    Article  PubMed  CAS  Google Scholar 

  • 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 5:1157–1165

    Article  PubMed  CAS  Google Scholar 

  • 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 16:3–10

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan

    Hirokazu Tanaka & Ichiro Taniuchi

Authors
  1. Hirokazu Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ichiro Taniuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ichiro Taniuchi .

Editor information

Editors and Affiliations

  1. Department of Developmental Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany

    Thomas Boehm

  2. Institute for Genome Research, Division of Experimental Immunology, University of Tokushima, Tokushima, Japan

    Yousuke Takahama

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Tanaka, H., Taniuchi, I. (2013). The CD4/CD8 Lineages: Central Decisions and Peripheral Modifications for T Lymphocytes. In: Boehm, T., Takahama, Y. (eds) Thymic Development and Selection of T Lymphocytes. Current Topics in Microbiology and Immunology, vol 373. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2013_323

Download citation

Publish with us

Policies and ethics

Search

Navigation