Immunologic Research

, Volume 27, Issue 2–3, pp 513–520 | Cite as

Genetic analysis of CD28 signaling

Article

Abstract

T cell activation is central to initiating an immune response. Two signals are required: an antigen-specific signal through the T cell receptor (TCR) and an antigen-independent costimulatory signal, primarily through CD28 in naïve T cells. Although many of the molecules involved in TCR signal transduction have been identified, the signaling pathways downstream of CD28 involved in costimulation are not well-defined. Through mutagenesis, we have generated a panel of Jurkat T cell lines in which CD28 costimulation fails to upregulate the RE/AP composite element of the IL-2 promoter. Biochemical analysis and genetic rescue of the defects in these cell lines will lead to a better understanding of CD28 signal transduction.

Key Words

CD28 Signal transduction RE/AP 

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References

  1. 1.
    Chambers CA, Allison JP: Costimulation in T cell responses. Curr Opin Immunol 1997;9: 396–404.PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz RH: T cell clomalanergy. Curr Opin Immunol 1997;9: 351–357.PubMedCrossRefGoogle Scholar
  3. 3.
    Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP: CD28-mediated signaling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992;356:607–609.PubMedCrossRefGoogle Scholar
  4. 4.
    June CH, Bluestone JA, Nadler LM, Thompson CB: The B7 and CD28 receptor families. Immunology Today 1994;15:321–331.PubMedCrossRefGoogle Scholar
  5. 5.
    Walts TH, DeBenedette MA: T cell co-stimulatory molecules other than CD28. Curr Opimm 1999;11: 286–293.Google Scholar
  6. 6.
    Borriello F, Sethna MP, Boyd SD, et al.: B7-1 and B7-2 have overlapping, critical roles for immuno globulin class switching and germinal center formation. Immunity 1997;6:303–313.PubMedCrossRefGoogle Scholar
  7. 7.
    Green JM, Noel PJ, Sperling AI, Waluras TL, Gray GS, Bluestone JA, Thompson CB: Absence of B7-dependent resporses in CD 28-deficient mice. Immunity 1994;1: 501–508.PubMedCrossRefGoogle Scholar
  8. 8.
    Shahinian A, Pfeffer K, Lee KP, et al.: Differential T cell costimulatory requirements in CD28-deficient mice. Science 1993; 261: 609–612.PubMedCrossRefGoogle Scholar
  9. 9.
    Riegel JS, Corthesy B, Flanagan WM, Crabtree GR: Regulation of the interleukin-2 gene. Chem Immunol 1992;51:266–298.PubMedCrossRefGoogle Scholar
  10. 10.
    Fraser JD, Irving BA, Crabtree GR, Weiss A: Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science 1991;251:313–316.PubMedCrossRefGoogle Scholar
  11. 11.
    Shapiro VS, Truitt KE, Imboden JB, Weiss A: CD28 mediates transcriptional upregualtion of the interleukin-2 (IL-2) promoter through a composite element containing the CD28R Eand NF-IL-2B AP-1 sites. Mol Cell Biol 1997; 17:4051–4058.PubMedGoogle Scholar
  12. 12.
    Shapiro VS, Mollenauer MN, Weiss A: Endo genous CD28 expressed on myeloma cells upregulates interleukin-8 production: implications for multiple myeloma progression. Blood 2001;98: 187–193.PubMedCrossRefGoogle Scholar
  13. 13.
    Shapiro VS, Mollenauer MN, Weiss A: Nuclear factor of activated T cells and AP-1 are insufficient for IL-2 promoter activation: requirement for CD28 up-regulation of RE/AP. J Immunol 1998;161: 4051–4058.Google Scholar
  14. 14.
    Holdorf AD, Kanagawa O, A.S. Shaw AS: CD28 and T cell co-stimulation. Rev Immunogen 2000;2:175–184.Google Scholar
  15. 15.
    Ward SG: CD28: a signaling perspective. Biochem J 1996;318:361–377.PubMedGoogle Scholar
  16. 16.
    Ruland J, Duncan GS, Elia A, et al.: Bc110 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 2001;104:33–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Sun Z, Arendt CW, Ellmeier W, et al.: PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature lymphocytes. Nature 2000;404:402–407.PubMedCrossRefGoogle Scholar
  18. 18.
    Bachmaier K, Krawczyk C, Kozieradzki I, et al.: Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cb1-b. Nature 2000; 403:211–216.PubMedCrossRefGoogle Scholar
  19. 19.
    Chiang Y, Kole HK, Brown K, et al.: Cb1-b regulates the CD28 dependence of T-cell activation. Nature 2000;403:216–220.PubMedCrossRefGoogle Scholar
  20. 20.
    Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A: Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN gamma but not Th2 cytokines. Nat Immunol 2001;2:37–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Burr JS, Savage NDL Messah GE, Kimzey SL, Shaw AS, Green JM: Distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL. J. Immunol. 2001; 166:5331–5335.PubMedGoogle Scholar
  22. 22.
    Harada Y, Tolishima M, Matsumoto Y, et al.: Critical requirement for the membrane-proximal cytosolic tyrosine residue for CD28-mediated costimulation in vivo. J Immunol 2001;166: 3797–3803.PubMedGoogle Scholar
  23. 23.
    Okkenhaug K, Wu L, Garza KM, et al.: A point mutation in CD28 distinguishes proliferative signals from survival signals. Nat Immunol 2001;2:325–332.PubMedCrossRefGoogle Scholar
  24. 24.
    Sadra A, Cinek T, Arellano JL, Shi J, Truitt KE, Imboden JB: Identification of tyrosine phosphorylation sites in the CD28 cytoplasmic domain and their role in the costimulation of Jurkat T cells. J Immunol 1999;162:1966–1973.PubMedGoogle Scholar
  25. 25.
    Chuang E, Fisher TS, Morgan RW, et al.: The CD28 and CTLA-4 receptors associate with theserine/threonine phosphatase PP2A. Immunity 2000;13:313–322.PubMedCrossRefGoogle Scholar
  26. 26.
    Marengere LE, Okkenhaug K, Clavreul A, Couez D, Gibson S, Mills GB, Rottapel R: The SH3 domain of Itk/Emt binds to proline-rich sequences in the cytoplasmic domain of the T cell costimulatory receptor CD28. J Immunol 1997;159:3220–3229.PubMedGoogle Scholar
  27. 27.
    Raab M, Cai YC, Bunnell SC, Heyeck SD, Berg LJ, Rudd CE: p56lck and p59fyn regulate CD28 binding to phosphatidy linositol 3-kinase, growth factor receptor-bound protein GRB-2 and T cell-specific ptoein-tyrosine kinase ITK: implications for T cell costimulation. Proc Natl Acad Sci USA 1995;92:8891–8895.PubMedCrossRefGoogle Scholar
  28. 28.
    Holdorf AD, Green JM, Levin SD, et al.: Proline residues in CD28 and the Src Homology (SH) 3 domain of Lck are required for T cell costimulation. J. Exp Med 1999;190: 375–384.PubMedCrossRefGoogle Scholar
  29. 29.
    Goldsmith MA, Weiss A: Isolation and characterization of a T-lymphocyte somatic mutant with altered signal transduction by the antigen receptor. Proc Natl Acad Sci USA 1987;84:6879–6883.PubMedCrossRefGoogle Scholar
  30. 30.
    Finco TS, Kadlecek T, Zhang W, Samelson LE, Weiss A: LAT is required for TCR-mediated activation of PLC gammal and the Ras pathway. Immunity 1998;9: 617–626.PubMedCrossRefGoogle Scholar
  31. 31.
    Irvin BJ, Williams BL, Nilson AE, Maynor HO, Abraham RT: Pleitropic contributions of phospholipase C-gamma 1 (PLC-gammal) to T-cell antigen receptor-mediated signaling: reconstitution studies of a PLC-gammal-deficient Jurkat T-cell line. Mol Cell Biol 2000;20: 9149–9161.PubMedCrossRefGoogle Scholar
  32. 32.
    Straus DB, Weiss A: Genetic evidence for the involvement of the ick tyrosine kinase in signal transduction through the T cell antigen receptor. Cell 1992;70:585–593.PubMedCrossRefGoogle Scholar
  33. 33.
    Williams BL, Schreiher KL, Zhang W, Wange RL, Samelson LE, Leibson PJ, Abraham RT: Genetic evidence for differential coupling of Syk family kinases to the T-cell receptor, reconstitution studies in a ZAP-70 deficient Jurkat T-cell line. Mol Cell Biol 1998;18: 1388–1399.PubMedGoogle Scholar
  34. 34.
    Yablorski D, Kuhne MR, Kadlecek T, Weiss A: Uncoupling of nonreceptor kinases from PLC-gammal in an SLP-76-deficient T cell. Science 1998;281:413–416.CrossRefGoogle Scholar
  35. 35.
    Iwashima M, Takamatsu M, Yamagishi H, et al.: Genetic evidence for She requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression. Proc Natl Acad Sci USA 2002;99: 4544–4549.PubMedCrossRefGoogle Scholar
  36. 36.
    Clements JL, Yang B, Ross-Barta SE, Eliason SL, Hrstka RF, Williamson RA, Koretzky GA: Requirement for the leukocyte-specificadapter protein SLP-76 for normal T cell development. Science 1998;281:416–419.PubMedCrossRefGoogle Scholar
  37. 37.
    Molina TJ, Kishihara K, Siderovski DP, et al.: Profound block in thymocyte development in mice lacking p56 lck. Nature 1992;357: 161–164.PubMedCrossRefGoogle Scholar
  38. 38.
    Negishi I, Motoyama N, Nakavama K, et al.: Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 1995;376:435–438.PubMedCrossRefGoogle Scholar
  39. 39.
    Pivniouk V, Tsitsikov E, Swinton P, Rathbun G, Alt FW, Geha RS: Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 1998;94:229–238.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang W, Sommers CL, Burshtyn DN, et al.: Essential role of LAT in T cell development. Immunity 1999;10:323–332.PubMedCrossRefGoogle Scholar
  41. 41.
    Stark GR, Gudkov AV: Forward genetic analysis in mammalian cells: functional approaches to gene discovery. Hum Mol Gen 1999;8:1925–1938.PubMedCrossRefGoogle Scholar
  42. 42.
    Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D, Gerondakis S: Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 1995;9:1965–1977.PubMedGoogle Scholar
  43. 43.
    Butscher WG, Powers C, Olive M, Virson C, Gardner K: Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB:2. J Biol Chem 1998;273:552–560.PubMedCrossRefGoogle Scholar
  44. 44.
    McGuire KL, Iacobelli M: Involvement of Rel, Fos and Jun proteins in binding activity to the IL-2 promoter CD28 response element/AP-1 sequence in human T cells. J Immunol 1997;159: 1319–1327.PubMedGoogle Scholar
  45. 45.
    Sun P, Dong P, Dai K, Hannon GJ, Beach D: p53-independent role of MDM2 in TGF-betal resistance. Science 1998;282:2270–2272.PubMedCrossRefGoogle Scholar
  46. 46.
    Holland SJ, Liao XC, Mendenhall MK, et al.: Functional cloning of Srelike adaptor prote in-2 (SLAP-2), a novel inhibitor of antigen receptor signaling. J Exp Med 2001;194: 1263–1276.PubMedCrossRefGoogle Scholar
  47. 47.
    Mahlmann S, McLaughlin J, Afar DE, Mohn R, Kay RJ, Witte ON: Dissection of signaling pathways and cloning of new signal transducers in tyrosine kinase-induced pathways by genetic selection. Leukemia 1998;12:1858–1865.PubMedCrossRefGoogle Scholar
  48. 48.
    Velazquez L, Fellous M, Stark GR, Pellegrini S: A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell 1992;70: 313–322.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphia

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