The Regulation and Function of the CD4 Coreceptor During T Lymphocyte Development

  • N. Killeen
  • D. R. Littman
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 205)


The progression of thymocytes through sequential developmental stages is marked by an ordered pattern of expression of many different cell surface molecules (Kruisbeek 1993). Of these, the CD4 and CD8 glycoproteins are noteworthy because their differential expression defines the two major lineages of mature peripheral T cells (Swain 1983). Although mature cells express one molecule or the other, the large majority of immature thymocytes expresses both CD4 and CD8. These double positive (DP) cells are subjected to a stringent selection process which favors survival of the few cells that can interact productively with host MHC molecules (Hogquist et al. 1994; von Boehmer 1994). Down-regulation of either CD4 or CD8 accompanies positive selection and precedes the emergence of mature cells with distinct effector functions.


Double Positive Thymic Selection Thymocyte Development Double Positive Thymocyte Thymocyte Selection 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aldrich CJ, Hammer RE, Jones-Youngblood S, Koszinowski U, Hood L, Stroynowski I, Forman J (1991) Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the alpha 3 domain of MHC I molecules. Nature 352: 718–721PubMedCrossRefGoogle Scholar
  2. Bank I, Chess L (1985) Perturbation of the T4 molecule transmits a negative signal to T cells. J Exp Med 162: 1294–1303PubMedCrossRefGoogle Scholar
  3. Baron A, Hafen K, von Boehmer H (1994) A human CD4 transgene rescues CD4-CD8+ cells in beta 2-microglobulin-deficient mice. Eur J Immunol 24: 1933–1936PubMedCrossRefGoogle Scholar
  4. Bekoff M, Kakiuchi T, Grey HM (1985) Accessory cell function in the Con A response: role of la-positive and la-negative accessory cells. J Immunol 134: 1337–1342PubMedGoogle Scholar
  5. Bendelac A, Matzinger P, Seder RA, Paul WE, Schwartz RH (1992) Activation events during thymic selection. J Exp Med 175: 731–742PubMedCrossRefGoogle Scholar
  6. Benoist C, Mathis D (1994) T cell receptors-the end of a frustrating search. Curr Biol 4: 821–823PubMedCrossRefGoogle Scholar
  7. Blum MD, Wong GT, Higgins KM, Sunshine MJ, Lacy E (1993) Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. J Exp Med 177: 1343–1358PubMedCrossRefGoogle Scholar
  8. Borgulya P, Kishi H, Muller U, Kirberg J, von Boehmer H (1991) Development of the CD4 and CD8 lineage T cells: instruction versus selection. EMBO J 10: 913–918PubMedGoogle Scholar
  9. Chan IT, Limmer A, Louie MC, Bullock ED, Fung-Leung W-P, Mak TW, Loh DY (1993a) Thymic selection of cytotoxic T cells independent of CD8a-Lck association. Science 261: 1581–1584PubMedCrossRefGoogle Scholar
  10. Chan SH, Cosgrove D, Waltzinger C, Benoist C, Mathis D (1993b) Another view of the selective model of thymocyte selection. Cell 73: 225–236PubMedCrossRefGoogle Scholar
  11. Chan SH, Waltzinger C, Baron A, Benoist C, Mathis D (1994) Role of coreceptors in positive selection and lineage commitment. EMBO J 13: 4482–4489PubMedGoogle Scholar
  12. Collins TL, Uniyal S, Shin J, Strominger JL, Mittler RS, Burakoff SJ (1992) p56lck association with CD4 is required for the interaction between CD4 and the TCR/CD3 complex and for optimal antigen stimulation. J Immunol 148: 2159–2162Google Scholar
  13. Connolly JM, Hansen TH, Ingold AL, Potter TA (1990) Recognition by CD8 on cytotoxic T lymphocytes is ablated by several substitutions in the class I alpha 3 domain: CD8 and the T - cell receptor recognize the same class I molecule. Proc Natl Acad Sci USA 87: 2137–2141PubMedCrossRefGoogle Scholar
  14. Corbella P, Moskophidis D, Spanopoulou E, Mamalaki C, Tolaini M, Itano A, Lans D, Baltimore D, Robey E, Kioussis D (1994) Functional commitment to helper T cell lineage precedes positive selection and is independent of T cell receptor MHC specificity. Immunity 1: 269–276PubMedCrossRefGoogle Scholar
  15. Crocker PR, Jefferies WA, Clark SJ, Chung LP, Gordon S (1987) Species heterogeneity in macrophage expression of the CD4 antigen. J Exp Med 166: 613–618PubMedCrossRefGoogle Scholar
  16. Crump AL, Grusby MJ, Glimcher LH, Cantor H (1993) Thymocyte development in major histocompatibility complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages. Proc Natl Acad Sci USA 90: 10739–10743PubMedCrossRefGoogle Scholar
  17. Davis CB, Littman DR (1994) Thymocyte lineage commitment: is it instructed or stochastic? Curr Opin Immunol 6: 266–272PubMedCrossRefGoogle Scholar
  18. Davis CB, Killeen N, Crooks MEC, Raulet D, Littman DR (1993) Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73: 237–247PubMedCrossRefGoogle Scholar
  19. Fowlkes BJ, Schwartz RH, Pardoll DM (1988) Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage. Nature 334: 620–623PubMedCrossRefGoogle Scholar
  20. Frederickson GG, Basch RS (1989) L3T4 antigen expression by hemopoietic precursor cells. J Exp Med 169: 1473–1478PubMedCrossRefGoogle Scholar
  21. Fung-Leung WP, Schilham MW, Rahemtulla A, Kundig TM, Vollenweider M, Potter J, van Ewijk W, Mak TW (1991) CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65: 443–449PubMedCrossRefGoogle Scholar
  22. Fung-Leung WP, Wallace VA, Gray D, Sha WC, Pircher H, Teh HS, Loh DY, Mak TW (1993) CD8 is needed for positive selection but differentially required for negative selection of T cells during thymic ontogeny. Eur J Immunol 23: 212–216PubMedCrossRefGoogle Scholar
  23. Gillespie FP, Doros L, Vitale J, Blackwell C, Gosselin J, Snyder BW, Wadsworth SC (1993) Tissue-specific expression of human CD4 in transgenic mice. Mol Cell Biol 13: 2952–2958PubMedGoogle Scholar
  24. Godfrey Dl, Kennedy J, Mombaerts P, Tonegawa S, Zlotnik A (1994) Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8-thymocyte differentiation. J Immunol 152: 4783–4792PubMedGoogle Scholar
  25. Gratiot-Deans J, Ding L, Turka LA, Nunez G (1993) bcl-2 proto-oneogene expression during human T cell development. Evidence for biphasic regulation. J Immunol 151: 83–91PubMedGoogle Scholar
  26. Groettrup M, Ungewiss K, Azogui O, Palacios R, Owen MJ, Hayday AC, von Boehmer H (1993) A novel disulfide-linked heterodimer on pre-T cells consists of the T cell receptor beta chain and a 33 kd glycoprotein. Cell 75: 283–294PubMedCrossRefGoogle Scholar
  27. Hanna Z, Simard C, Laperriere A, Jolicoeur P (1994) Specific expression of the human CD4 gene in mature CD4+ CD8 and immature CD4+CD8+ T cells and in macrophages of transgenic mice. Mol Cell Biol 14: 1084–1094PubMedGoogle Scholar
  28. Hogquist KA, Jameson SC, Bevan MJ (1994) The ligand for positive selection of T lymphocytes in the thymus. Curr Opin Immunol 6: 273–278PubMedCrossRefGoogle Scholar
  29. Hu JS, Olson EN, Kingston RE (1992) HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Mol Cell Biol 12: 1031–1042PubMedGoogle Scholar
  30. Ingold AL, Landel C, Knall C, Evans GA, Potter TA (1991) Co-engagement of CD8 with the T cell receptor is required for negative selection. Nature 352: 721–723PubMedCrossRefGoogle Scholar
  31. Itano A, Kioussis D, Robey E (1994) Stochastic component to development of class I major histocompatibility complex-specific T cells. Proc Natl Acad Sci USA 91: 220–224PubMedCrossRefGoogle Scholar
  32. Janeway CA Jr (1992) The T cell receptor as a multicomponent signalling machine. Annu Rev Immunol 10: 645–674PubMedCrossRefGoogle Scholar
  33. Kazazi F, Mathijs JM, Foley P, Cunningham AL (1989) Variations in CD4 expression by human monocytes and macrophages and their relationships to infection with the human immunodeficiency virus. J Gen Virol 70: 2661–2672PubMedCrossRefGoogle Scholar
  34. Kearse KP, Roberts JL, Munitz Tl, Wiest DL, Nakayama T, Singer A (1994) Developmental regulation of alpha-beta T cell antigen receptor expression results from differential stability of nascent TCR-alpha proteins within the endoplasmic reticulum of immature and mature T cells. EMBO J 13: 4504–4514PubMedGoogle Scholar
  35. Killeen N, Littman DR (1993) Helper T cell development in the absence of CD4-p56lck association. Nature 364: 729–732PubMedCrossRefGoogle Scholar
  36. Killeen N, Moriarty A, Teh HS, Littman DR (1992) Requirement for CD8-MHC class I interaction in positive and negative selection of developing T cells. J Exp Med 176: 89–97PubMedCrossRefGoogle Scholar
  37. Killeen N, Sawada S, Littman DR (1993) Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J 12: 1547–1553PubMedGoogle Scholar
  38. Kruisbeek AM (1993) Development of αβ T cells. Curr Opin Immunol 5: 227–234PubMedCrossRefGoogle Scholar
  39. Lee NA, Loh DY, Lacy E (1992) CD8 surface levels alter the fate of aß TCR expressing thymocytes in transgenic mice. J Exp Med 175: 1013–1025PubMedCrossRefGoogle Scholar
  40. Locksley RM, Reiner SL, Hatam F, Littman DR, Killeen N (1993) Helper T cells without CD4: control of leishmaniasis in CD4-deficient mice. Science 261: 1448–1451PubMedCrossRefGoogle Scholar
  41. Lucey DR, Dorsky Dl, Nicholson-Weller A, Weller PF (1989) Human eosinophils express CD4 protein and bind human immunodeficiency virus 1 gp120. J Exp Med 169: 327–332PubMedCrossRefGoogle Scholar
  42. MacDonald HR, Hengartner H, Pedrazzini T (1988) Intrathymic deletion of self-reactive cells prevented by neonatal anti-CD4 antibody treatment. Nature 335: 174PubMedCrossRefGoogle Scholar
  43. Mombaerts P, Clarke AR, Rudnicki MA, lacomini J, Itohara S, Lafaille JJ, Wang L, Ichikawa Y, Jaenisch R, Hooper ML, Tonegawa S (1992) Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature 360: 225–231PubMedCrossRefGoogle Scholar
  44. Mombaerts P, Anderson SJ, Perlmutter RM, Mak TW, Tonegawa S (1994) An activated Ick transgene promotes thymocyte development in RAG-1 mutant mice. Immunity 1: 261–267PubMedCrossRefGoogle Scholar
  45. Moore NC, Anderson G, Williams GT, Owen JJ, Jenkinson EJ (1994) Developmental regulation of bcl-2 expression in the thymus. Immunology 81: 115–119PubMedGoogle Scholar
  46. Murre C, McCaw PS, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, My, and myc proteins. Cell 56: 777–783PubMedCrossRefGoogle Scholar
  47. Newell MK, Haughn LJ, Maroun CR, Julius MH (1990) Death of mature T cells by separate ligation of CD4 and the T cell receptor for antigen. Nature 347: 286–289PubMedCrossRefGoogle Scholar
  48. Paillard F, Sterkers G, Vaquero C (1990) Transcriptional and post-transcriptional regulation of T, CD4 and CD8 gene expression during activation of normal human T lymphocytes. EMBO J 9: 1867–1872PubMedGoogle Scholar
  49. Rahemtulla A, Fung-Leung WP, Schilham MW, Kundig TM, Samhara SR, Narendran A, Arabian A, Wakeham A, Paige CJ, Zinkernagel RM, Miller RG, Mak TW (1991) Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353: 180–184PubMedCrossRefGoogle Scholar
  50. Rahemtulla A, Kundig TM, Narendran A, Bachmann MF, Julius M, Paige CJ, Ohashi PS, Zinkernagel RM, Mak TW (1994) Class II major histocompatibility complex-restricted T cell function in CD4-deficient mice. Eur J Immunol 24: 2213–2218PubMedCrossRefGoogle Scholar
  51. Ramsdell F, Fowlkes BJ (1989) Engagement of CD4 and CD8 accessory molecules is required for T cell maturation. J Immunol 143: 1467–1471PubMedGoogle Scholar
  52. Robey E, Fowlkes BJ, Gordon JW, Kioussis D, von Boehmer H, Ramsdell F, Axel R (1991) Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CDS lineage. Cell 64: 99–107PubMedCrossRefGoogle Scholar
  53. Robey E, Itano A, Fanslow WC, Fowlkes BJ (1994) Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J Exp Med 179: 1997–2004PubMedCrossRefGoogle Scholar
  54. Robey EA, Ramsdell F, Kioussis D, Sha WC, Loh DY, Axel R, Fowlkes BJ (1992) The level of CD8 expression can determine the outcome of thymic selection. Cell 69: 1089–1096PubMedCrossRefGoogle Scholar
  55. Rothenberg EV (1994) Signaling mechanisms in thymocyte selection. Curr Opin Immunol 6: 257–265PubMedCrossRefGoogle Scholar
  56. Salmon P, Giovane A, Wasylyk B, Klatzmann D (1993) Characterization of the human CD4 gene promoter: transcription from the CD4 gene core promoter is tissue-specific and is activated by Ets proteins. Proc Natl Acad Sci USA 90: 7739–7743PubMedCrossRefGoogle Scholar
  57. Salter RD, Benjamin RJ, Wesley PK, Buxton SE, Garrett TP, Clayberger C, Krensky AM, Norment AM, Littman DR, Parham P (1990) A binding site for the T-cell co-receptor CD8 on the alpha 3 domain of HLA-A2. Nature 345: 41–46PubMedCrossRefGoogle Scholar
  58. Sands JF, Nikolic-Zugic J (1992) T cell-specific protein-DNA interactions occurring at the CD4 locus: identification of possible transcriptional control elements of the murine CD4 gene. Int Immunol 4: 1183–1194PubMedCrossRefGoogle Scholar
  59. Sawada S, Littman DR (1991) Identification and characterization of a T cell-specific enhancer adjacent to the murine CD4 gene. Mol Cell Biol 11: 5506–5515PubMedGoogle Scholar
  60. Sawada S, Littman DR (1993) A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer arid regulates its activity in T-cell lines. Mol Cell Biol 13: 5620–5628PubMedGoogle Scholar
  61. Sawada S, Scarborough JD, Killeen N, Littman DR (1994) A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77: 917–929PubMedCrossRefGoogle Scholar
  62. Schonrich G, strauss G, Muller KP, Dustin L, Loh DY, Auphan N, Schmitt-Verhulst AM, Arnold B, Hammerling GJ (1993) Distinct requirements of positive and negative selection for selecting cell type and CD8 interaction. J Immunol 151: 4098–4105PubMedGoogle Scholar
  63. Seong RH, Chamberlain JW, Parnes JR (1992) Signal for T-cell differentiation to a CD4 cell lineage is delivered by a CD4 transmembrane region and/or cytoplasmic tail. Nature 356: 718–720PubMedCrossRefGoogle Scholar
  64. Siu G, Wurster AL, Lipsick JS, Hedrick SM (1992) Expression of the CD4 gene requires a Myb transcription factor. Mol Cell Biol 12: 1592–1604PubMedGoogle Scholar
  65. Siu G, Wurster AL, Duncan DD, Soliman TM, Hedrick SM (1994) A transcriptional silencer controls the developmental expression of the CD4 gene. EMBO J 13: 3570–3579PubMedGoogle Scholar
  66. Spits H (1994) Early stages in human and mouse T - cell development. Curr Opin Immunol 6: 212–221PubMedCrossRefGoogle Scholar
  67. Swain SL (1983) T cell subsets and the recognition of the MHC class. Immunol Rev 74: 129–142PubMedCrossRefGoogle Scholar
  68. Swat W, Dessing M, von Boehmer H, Kisielow P (1993) CD69 expression during selection and maturation of CD4+CD8+ thymocytes. Eur J Immunol 23: 739–746PubMedCrossRefGoogle Scholar
  69. Takahama Y, Singer A (1992) Post-transcriptional regulation of early T cell development by T cell receptor signals. Science 258: 1456–1462PubMedCrossRefGoogle Scholar
  70. Tite JP, Sloan A, Janeway CAJ (1986) The role of L3T4 in T cell activation: L3T4 may be both an la-binding protein and a receptor that transduces a negative signal. Mol Cell Immunol 2: 179–190Google Scholar
  71. Travis A, Amsterdam A, Belanger C, Grosschedl R (1991) LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function. Genes Dev 5: 880–894PubMedCrossRefGoogle Scholar
  72. Turka LA, Schatz DG, Oettinger MA, Chun JJ, Gorka C, Lee K Mormack WT, Thompson CB (1991) Thymocyte expression of RAG-1 and RAG-2: termination by T cell receptor cross-linking. Science 253: 778–781PubMedCrossRefGoogle Scholar
  73. van Meerwijk JPM, Germain RN (1993) Development of mature CD8+ thymocytes: selection rather than instruction? Science 261: 911–915PubMedCrossRefGoogle Scholar
  74. Veis DJ, Sentman CL, Bach EA, Korsmeyer SJ (1993) Expression of the Bcl-2 protein in murine and human thymocytes and in peripheral T lymphocytes. J Immunol 151: 2546–2554PubMedGoogle Scholar
  75. von Boehmer H (1994) Positive selection of lymphocytes. Cell 76: 219–228CrossRefGoogle Scholar
  76. Wallace VA, Rahemtulla A, Timms E, Penninger J, Mak TW (1992) CD4 expression is differentially required for deletion of MLS-1a-reactive T cells. J Exp Med 176: 1459–1463PubMedCrossRefGoogle Scholar
  77. Wassmer P, Chan C, Logdberg L, Shevach EM (1985) Role of the L3T4-antigen in T cell activation. II. Inhibition of T cell activation by monoclonal anti-L3T4 antibodies in the absence of accessory cells. J Immunol 135: 2237–2242PubMedGoogle Scholar
  78. Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S (1991) The my gene family: nodal point during specification of the muscle cell lineage. Science 251: 761–766PubMedCrossRefGoogle Scholar
  79. Wu L, Scollay R, Egerton M, Pearse M, Spangrude GJ, Shortman K (1991) CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature 349: 71–74PubMedCrossRefGoogle Scholar
  80. Wurster AL, Siu G, Leiden JM, Hedrick SM (1994) Elf-1 binds to a critical element in a second CD4 enhancer. Mol Cell Biol 14: 6452–6463PubMedGoogle Scholar
  81. Xu H, Littman DR (1993) A kinase-independent function of Lck in potentiating antigen-specific T cell 106 activation. Cell 74: 633–643PubMedCrossRefGoogle Scholar
  82. Zúñiga-Pflücker JC, Jones LA, Longo DL, Kruisbeek AM (1990) CD8 is required during positive selection of CD4/CD8+ T cells. J Exp Med 171: 427–437CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • N. Killeen
    • 1
  • D. R. Littman
    • 2
  1. 1.Department of Microbiology and ImmunologyUniversity of California at San FranciscoSan FranciscoUSA
  2. 2.Molecular Pathogenesis Program and The Howard Hughes Medical Institute, The Skirball Institute of Biomolecular MedicineNew York University Medical CenterNew YorkUSA

Personalised recommendations