Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Anna Morath
  • Sumit Deswal
  • Wolfgang W. A. SchamelEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_507


 CD3γ;  CD3δ;  CD3ε;  T3


CD3 is a complex of three type 1 transmembrane (TM) proteins expressed in T cells and most likely also in some neurons: CD3γ, CD3δ, and CD3ε.  CD3ζ (  CD247) is described in a separate chapter due to significant differences compared to CD3γ, CD3δ, and CD3ε. The CD3γ and CD3δ chains are glycoproteins, each of which forms a heterodimer with the nonglycosylated CD3ε chain. These chains associate with TCRαβ and a CD3ζζ dimer to form the αβ T cell antigen receptor (TCR) complex in αβ T cells (Figs. 1 and 2). The CD3 chains and CD3ζζ also associate with pTα and TCRβ to form the pre-TCR and with TCRγδ to form the γδTCR in the case of pre-T cells and γδ T cells, respectively. In murine but not human TCRγδs the CD3εδ heterodimer is replaced by a second CD3εγ heterodimer (Siegers et al. 2007). Each of the CD3 subunits possesses an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail, which becomes phosphorylated upon antigen...
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  1. Alarcon B, Berkhout B, et al. Assembly of the human T cell receptor-CD3 complex takes place in the endoplasmic reticulum and involves intermediary complexes between the CD3-gamma.delta.epsilon core and single T cell receptor alpha or beta chains. J Biol Chem. 1988;263(6):2953.PubMedPubMedCentralGoogle Scholar
  2. Arnaiz-Villena A, Timon M, et al. Brief report: primary immunodeficiency caused by mutations in the gene encoding the CD3gamma subunit of the T-lymphocyte receptor. N Engl J Med. 1992;327:529–33.PubMedCrossRefGoogle Scholar
  3. Arnett KL, Harrison SC, et al. Crystal structure of a human CD3-epsilon/delta dimer in complex with a UCHT1 single-chain antibody fragment. Proc Natl Acad Sci USA. 2004;101(46):1626826886.CrossRefGoogle Scholar
  4. Blanco R, Borroto A, et al. Conformational changes in the T cell receptor differentially determine T cell subset development in mice. Sci Signal. 2014;7(354):ra115.PubMedCrossRefGoogle Scholar
  5. Borroto A, Arellano I, et al. Nck recruitment to the TCR required for ZAP70 activation during thymic development. J Immunol. 2013;190(3):1103–12.PubMedCrossRefGoogle Scholar
  6. Borroto A, Abia D, et al. Crammed signaling motifs in the T-cell receptor. Immunol Lett. 2014a;161(1):113–7.PubMedCrossRefGoogle Scholar
  7. Borroto A, Arellano I, et al. Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. J Immunol. 2014b;192(5):2042–53.PubMedCrossRefGoogle Scholar
  8. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7(8):622–6.PubMedCrossRefGoogle Scholar
  9. Dadi HK, Simon AJ, et al. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficieny. N Engl J Med. 2003;349:1821.PubMedCrossRefGoogle Scholar
  10. Dave VP, Cao Z, et al. CD3 delta deficiency arrests development of the alpha beta but not the gamma delta T cell lineage. EMBO J. 1997;16(6):1360.PubMedPubMedCentralCrossRefGoogle Scholar
  11. de Saint Basile G, Geissmann F, et al. Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J Clin Invest. 2004;114(10):1512.PubMedCrossRefGoogle Scholar
  12. Deford-Watts LM, Tassin TC, et al. The cytoplasmic tail of the T cell receptor CD3 epsilon subunit contains a phospholipid-binding motif that regulates T cell functions. J Immunol. 2009;183(2):10552–10.CrossRefGoogle Scholar
  13. Delgado P, Cubelos B, et al. Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nat Immunol. 2009;10(8):880–8.PubMedCrossRefGoogle Scholar
  14. Dietrich J, Hou X, et al. CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor. EMBO J. 1994;13(9):2156–66.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Dopfer EP, Hartl FA, et al. The CD3 conformational change in the γδ T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing. Cell Rep. 2014;7(5):1704–15.PubMedCrossRefGoogle Scholar
  16. Doucey MA, Goffin L, et al. CD3 delta establishes a functional link between the T cell receptor and CD8. J Biol Chem. 2003;278(5):3257.PubMedCrossRefGoogle Scholar
  17. Fernández-Arenas E, Calleja E, et al. β-Arrestin-1 mediates the TCR-triggered re-routing of distal receptors to the immunological synapse by a PKC-mediated mechanism. EMBO J. 2014;33(6):559–77.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fernández-Malavé E, Wang N, et al. Overlapping functions of human CD3delta and mouse CD3gamma in alphabeta T-cell development revealed in a humanized CD3gamma-mouse. Blood. 2006;108(10):3420–7.PubMedCrossRefGoogle Scholar
  19. Gil D, Schamel WW, et al. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002;109(7):901–12.PubMedCrossRefGoogle Scholar
  20. Gobel TW, Dangy J-P. Evidence for a stepwise evolution of the CD3 family. J Immunol. 2000;164:879–83.PubMedCrossRefGoogle Scholar
  21. Haks MC, Krimpenfort P, et al. The CD3gamma chain is essential for development of both the TCRalphabeta and TCRgammadelta lineages. EMBO J. 1998;17(7):1871–82.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Hayes SM, Laky K, et al. Activation-induced modification in the CD3 complex of the gammadelta T cell receptor. J Exp Med. 2002;196(10):1355–61. Erratum in: J Exp Med 2002 Dec 16;196(12):1653.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Holst J, Wang H, et al. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat Immunol. 2008;9(6):658–66.PubMedCrossRefGoogle Scholar
  24. Kesti T, Ruppelt A, et al. Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3epsilon. J Immunol. 2007;179(2):878–85.PubMedCrossRefGoogle Scholar
  25. Kjer-Nielsen L, Dunstone MA, et al. Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. Proc Natl Acad Sci USA. 2004;101(20):7675.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Kung P, Goldstein G, et al. Monoclonal antibodies defining distinctive human T cell surface antigens. Science. 1979;206(4416):347–9.PubMedCrossRefGoogle Scholar
  27. Lauritsen JP, Bonefeld CM, et al. Masking of the CD3 gamma di-leucine-based motif by zeta is required for efficient T-cell receptor expression. Traffic. 2004;5(9):672–84.PubMedCrossRefGoogle Scholar
  28. Malissen M, Gillet A, et al. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 1995;14(19):4641–53.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Martín-Cófreces NB, Baixauli F, et al. End-binding protein 1 controls signal propagation from the T cell receptor. EMBO J. 2012;31(21):4140–52.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Martinez-Martin N, Risueno RM, et al. Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3epsilon. Sci Signal. 2009;2(83):ra43.PubMedCrossRefGoogle Scholar
  31. Molnár E, Swamy M, et al. Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J Biol Chem. 2012;287(51):42664–74.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Muñoz-Ruiz M, Ribot JC, et al. TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets. Nat Immunol. 2016;17(6):721–7.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Paensuwan P, Hartl FA, et al. Nck binds to the T cell antigen receptor using its SH3.1 and SH2 domains in a cooperative manner, promoting TCR functioning. J Immunol. 2016;196(1):448–58. Erratum in: J Immunol. 2016;196(11):4833.Google Scholar
  34. Recio MJ, Moreno-Pelayo MA, et al. Differential biological role of CD3 chains revealed by human immunodeficiencies. J Immunol. 2007;178(4):2556–64.PubMedCrossRefGoogle Scholar
  35. Reth M. Antigen receptor tail clue. Nature. 1989;338:383.PubMedCrossRefGoogle Scholar
  36. Roy E, Togbe D, et al. Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire. Proc Natl Acad Sci USA. 2010a;107(35):15529–34.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Roy E, Togbe D, et al. Fine tuning of the threshold of T cell selection by the Nck adapters. J Immunol. 2010b;185(12):7518–26.PubMedCrossRefGoogle Scholar
  38. Sancho J, Chatila T, et al. T-cell antigen receptor (TCR)-alpha/beta heterodimer formation is a prerequisite for association of CD3-zeta 2 into functionally competent TCR.CD3 complexes. J Biol Chem. 1989;264(34):20760.PubMedPubMedCentralGoogle Scholar
  39. Schamel WW, Alarcón B. Organization of the resting TCR in nanoscale oligomers. Immunol Rev. 2013;251(1):13–20.PubMedCrossRefGoogle Scholar
  40. Schamel WW, Arechaga I, et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med. 2005;202:493.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Shi X, Bi Y, et al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature. 2013;493(7430):111–5.PubMedCrossRefGoogle Scholar
  42. Siegers GM, Swamy M, et al. Different composition of the human and the mouse gammadelta T cell receptor explains different phenotypes of CD3gamma- and CD3delta-immunodeficiencies. J Exp Med. 2007;204(11):2537.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Soudais C, de Villartay J-P, et al. Independent mutations of the human CD3epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nat Genet. 1993;3:77.PubMedCrossRefGoogle Scholar
  44. Swamy M, Beck-Garcia K, et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity. 2016;44(5):1091–101.PubMedCrossRefGoogle Scholar
  45. Tunnacliffe A, Olsson C, et al. Organization of the human CD3 locus on chromosome 11. Eur J Immunol. 1988;18(10):1639–42.PubMedCrossRefGoogle Scholar
  46. Wang N, Wang B, et al. Expression of a CD3epsilon transgene in CD3 epsilon(null) mice does not restore CD3 gamma and delta expression but efficiently rescues T cell development from a subpopulation of prothymocytes. Int Immunol. 1998;10(12):1777–88.PubMedCrossRefGoogle Scholar
  47. Wang F, Beck-García K, et al. Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol. Nat Immunol. 2016;17(7):844–50.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Anna Morath
    • 1
    • 2
    • 3
    • 4
  • Sumit Deswal
    • 1
    • 5
    • 6
  • Wolfgang W. A. Schamel
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Immunology, Institute for Biology IIIUniversity of FreiburgFreiburgGermany
  2. 2.Centre for Biological Signaling Studies (BIOSS)University of FreiburgFreiburgGermany
  3. 3.Centre of Chronic Immunodeficiency (CCI)University Medical Center Freiburg and University of FreiburgFreiburgGermany
  4. 4.Spemann Graduate School of Biology and MedicineUniversity of FreiburgFreiburgGermany
  5. 5.Max Planck Institute of ImmunobiologyFreiburgGermany
  6. 6.Research Institute of Molecular PathologyViennaAustria