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Accessory molecule regulation of naive CD4 T cell activation

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Abstract

Naive CD4 T cell activation is a complex process involving many steps. T cell receptor (TCR) signals, provided by interaction with peptide/MHC on antigen-presenting cells (APC), control many events associated with activation. The extent of TCR signaling and the magnitude of the T cell response is in turn controlled by accessory molecules on APC, which stabilize T-APC interactions. Full T cell activation additionally requires multiple costimulatory signals, generated upon ligation of T cell coreceptors by accessory molecules, and these lead to IL-2 production, proliferation and differentiation of the naive cell into an effector state. This review summarizes the role played by accessory molecules in naive CD4 activation and discusses how integration of signals from these molecules, with signals from the TCR, may determine the outcome of T-APC interaction. The available data provide explanations for why only APC which express high levels of multiple costimulatory/adhesion molecules, such as dendritic cells and activated B cells, induce efficient naive T cell responses, and suggest that ICAM-1/LFA-1 and B7/CD28 interactions are major pathways used to initiate naive T cell activation.

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References

  1. Fitch FW, McKisic MD, Lancki DW, Gajewski TF: Differential regulation of murine T lymphocyte subsets. Annu Rev Immunol 1993; 11:29.

    Article  PubMed  CAS  Google Scholar 

  2. Clark EA, Ledbetter JA: How B and T cells talk to each other. Nature 1994;367:425.

    Article  PubMed  CAS  Google Scholar 

  3. Steinman RM, Young JW: Signals arising from antigen-presenting cells. Curr Opin Immunol 1991;3: 361.

    Article  PubMed  CAS  Google Scholar 

  4. Johnson JG, Jenkins MK: Accessory cell-derived signals required for T cell activation. Immunol Res 1993; 12:48.

    Article  PubMed  CAS  Google Scholar 

  5. Janeway CA Jr, Bottomly K: Signals and signs for lymphocyte responses. Cell 1994;76:275.

    Article  PubMed  CAS  Google Scholar 

  6. Mueller DL, Jenkins MK, Schwartz RH: Clonal expansion versus functional clonal inactivation: A costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 1989;7:445.

    PubMed  CAS  Google Scholar 

  7. Mueller DL, Jenkins MK: Molecular mechanisms underlying functional T-cell unresponsiveness. Curr Opin Immunol 1995;7:375.

    Article  PubMed  CAS  Google Scholar 

  8. Zhang X, Giangreco L, Broome HE, Dargan CM, Swain SL: Control of CD4 effector fate: TGFβ1 and IL-2 synergise to prevent apoptosis and promote effector expansion. J Exp Med 1995;182:699.

    Article  PubMed  CAS  Google Scholar 

  9. Swain SL, Bradley LM, Croft M, Tonkonogy S, Atkins G, Weinberg AD, Duncan DD, Hedrick SM, Dutton RW, Huston G: Helper T cell subsets: Phenotype, function and the role of lymphokines in regulating their development. Immunol Rev 1991;123:115.

    Article  PubMed  CAS  Google Scholar 

  10. Croft M: Activation of naive, memory and effector T cells. Curr Opin Immunol 1994;6:431.

    Article  PubMed  CAS  Google Scholar 

  11. Bretscher PA, Cohn M: A theory of self-nonself discrimination. Science 1970;169:1042.

    Article  PubMed  CAS  Google Scholar 

  12. Jenkins MK, Ashwell JD, Schwartz RH: Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol 1988; 140:3324.

    PubMed  CAS  Google Scholar 

  13. Bretscher P: The two-signal model of lymphocyte activation twenty-one years later. Immunol Today 1992;13:74.

    Article  PubMed  CAS  Google Scholar 

  14. Kearney ER, Pape KA, Loh DY, Jenkins MK: Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1994;1:327.

    Article  PubMed  CAS  Google Scholar 

  15. Littman DR: The structure of the CD4 and CD8 genes. Annu Rev Immunol 1987;5:561.

    Article  PubMed  CAS  Google Scholar 

  16. Collins TL, Kassner PD, Bierer BE, Burakoff SJ: Adhesion receptors in lymphocyte activation. Curr Opin Immunol 1994;6:385.

    Article  PubMed  CAS  Google Scholar 

  17. Allison JP: CD28-B7 interactions in T-cell activation. Curr Opin Immunol 1994;6:414.

    Article  PubMed  CAS  Google Scholar 

  18. Bluestone JA: New perspectives of CD28-B7 mediated T cell costimulation. Immunity 1995;2:555.

    Article  PubMed  CAS  Google Scholar 

  19. Dubey C, Croft M, Swain SL: Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. J Immunol 1995; 155:45.

    PubMed  CAS  Google Scholar 

  20. Damle NK, Klussman K, Linsley PS, Aruffo A: Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol 1992; 148:1985.

    PubMed  CAS  Google Scholar 

  21. Kato K, Koyanagi M, Okada H, Takanashi T, Wong YW, Williams AF, Okumura K, Yagita H: CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation. J Exp Med 1992;176:1241.

    Article  PubMed  CAS  Google Scholar 

  22. Lia Y, Jones B, Aruffo A, Sullivan KM, Linsley PS, Janeway CA Jr: Heat-stable antigen is a costimulatory molecule for CD4 T cell growth. J Exp Med 1992;175:437.

    Article  Google Scholar 

  23. Kobata T, Agematsu K, Kameoka J, Schlossman SF, Morimoto C: CD27 is a signal-transducing molecule involved in CD45RA+ naive T cell costimulation. J Immunol 1994; 153:5422.

    PubMed  CAS  Google Scholar 

  24. DeBenedette MA, Chu NR, Pollok KE, Hurtado J, Wade WF, Kwon BS, Watts TH: Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J Exp Med 1995;181:985.

    Article  PubMed  CAS  Google Scholar 

  25. Boussiotis VA, Freeman GJ, Gribben JG, Daley J, Gray G, Nadler LM: Activated human B lymphocytes express three CTLA-4 counter-receptors that costimulate T cell activation. Proc Natl Acad Sci USA 1993;90:11059.

    Article  PubMed  CAS  Google Scholar 

  26. Larsen CP, Ritchie SC, Hendrix R, Linsley PS, Hathcock KS, Hodes RJ, Lowry RP, Pearson TC: Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol 1994; 152:5208.

    PubMed  CAS  Google Scholar 

  27. Stack RM, Lenschow DJ, Gray GS, Bluestone JA, Fitch FW: IL-4 treatment of small splenic B cells induces costimulatory molecules B7-1 and B7-2. J Immunol 1994;152:5723.

    PubMed  CAS  Google Scholar 

  28. Lenschow DJ, Sperling AI, Cooke MP, Freeman G, Rhee L, Decker DC, Gray G, Nadler LM, Goodnow CC, Bluestone JA: Differential upregulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen. J Immunol 1994;153:1990.

    PubMed  CAS  Google Scholar 

  29. Dennig D, Lacerda J, Yan Y, Gasparetto C, O'Reilly RJ: ICAM-1 (CD54) expression on B lymphocytes is associated with their costimulatory function and can be increased by coactivation with 1L-1 and IL-7. Cell Immunol 1994;156: 414.

    Article  PubMed  CAS  Google Scholar 

  30. Steinman RM: The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271.

    Article  PubMed  CAS  Google Scholar 

  31. Croft M, Duncan DD, Swain SL: Response of naive antigen-specific CD4+ T cells in vitro: Characteristics and antigen presenting cell requirements. J Exp Med 1992;176:1431.

    Article  PubMed  CAS  Google Scholar 

  32. Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh C-S, Culpepper JA, Wysocka M, Trincheri G, Murphy KM, O'Garra A: Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 1995;154:5071.

    PubMed  CAS  Google Scholar 

  33. Finkelman FD, Lees A, Morris SC: Antigen presentation by B lymphocytes to CD4+ T lymphocytes in vivo: Importance for B lymphocyte and T lymphocyte activation. Semin Immunol 1992;4:247.

    PubMed  CAS  Google Scholar 

  34. Cassell DJ, Schwartz RH: A quantitative analysis of antigen-presenting cell functions: Activated B cells stimulate naive CD4 T cells but are inferior to dendritic cells in providing stimulation. J Exp Med 1994; 180:1829.

    Article  PubMed  CAS  Google Scholar 

  35. Croft M, Swain SL: Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines. J Immunol 1995; 154:4269.

    PubMed  CAS  Google Scholar 

  36. Eynon EE, Parker DC: Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 1992;175:131.

    Article  PubMed  CAS  Google Scholar 

  37. Ho WY, Cooke MP, Goodnow CC, Davis MM: Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells. J Exp Med 1994;179:1539.

    Article  PubMed  CAS  Google Scholar 

  38. Inaba K, Witmer-Pack M, Inaba M, Hathcock KS, Sakuta H, Azuma M, Yagita H, Okumura K, Linsley PS, Ikehara S, Muramatsu S, Hodes RJ, Steinman RM: The tissue distribution of the B7-2 costimulator in mice: Abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med 1994;180:1849.

    Article  PubMed  CAS  Google Scholar 

  39. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R: Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994; 1:793.

    Article  PubMed  CAS  Google Scholar 

  40. Krummel MF, Allison JP: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459.

    Article  PubMed  CAS  Google Scholar 

  41. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA: CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405.

    Article  PubMed  CAS  Google Scholar 

  42. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541.

    Article  PubMed  CAS  Google Scholar 

  43. Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M: CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol 1995; 154:97.

    PubMed  CAS  Google Scholar 

  44. Freeman GJ, Boussiotis VA, Anumanthan A, Bernstein GM, Ke X-Y, Rennert PD, Gray GS, Gribben JG, Nadler LM: B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 1995;2:523.

    Article  PubMed  CAS  Google Scholar 

  45. Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, Weiner HL, Nabavi N, Glimcher LH: B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapy. Cell 1995;80:707.

    Article  PubMed  CAS  Google Scholar 

  46. Damle NK, Linsley PS, Ledbetter JA: Direct helper T cell-induced B cell differentiation involves interaction between T cell antigen CD28 and B cell activation antigen B7. Eur J Immunol 1991;21:1277.

    Article  PubMed  CAS  Google Scholar 

  47. Linsley PS, Wallace PM, Johnson J, Gibson MG, Greene JL, Ledbetter JA, Singh C, Tepper MA: Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992;257:792.

    Article  PubMed  CAS  Google Scholar 

  48. Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA: Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig. Science 1992;257:789.

    Article  PubMed  CAS  Google Scholar 

  49. Finck BK, Linsley PS, Wofsy D: Treatment of murine lupus with CTLA4Ig. Science 1994;265:1225.

    Article  PubMed  CAS  Google Scholar 

  50. Jaiswal AI, Dubey C, Swain SL, Croft M: Regulation of CD40-ligand expression on naive CD4 T cells: A role for T cell receptor but not costimulatory signals. Int Immunol 1995;8:275.

    Article  Google Scholar 

  51. Green JM, Noel PJ, Sperling AI, Walunas TL, Gray GS, Bluestone JA, Thompson CB: Absence of B7-dependent responses in CD28-deficient mice. Immunity 1994;1:501.

    Article  PubMed  CAS  Google Scholar 

  52. Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak TW: Differential T cell costimulatory requirements in CD28-deficient mice. Science 1993;261:609.

    Article  PubMed  CAS  Google Scholar 

  53. Lucas PJ, Negishi I, Nakayama K, Fields LE, Loh DY: Naive CD28-deficient T cells can initiate but not sustain an in vitro antigen-specific immune response. J Immunol 1995; 154:5757.

    PubMed  CAS  Google Scholar 

  54. Poudrier J, Owens T: CD54/intercellular adhesion molecule 1 and major histocompatibility complex II signaling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation. J Exp Med 1994;179:1417.

    Article  PubMed  CAS  Google Scholar 

  55. Fischer H, Gjorloff A, Hedlund G, Hedman H, Lundgren E, Kalland T, Sjogren HO, Dohlsten M: Stimulation of human naive and memory T helper cells with bacterial superantigen. Naive CD4+45RA+T cells require a costimulatory signal mediated through the LFA-1/ICAM-1 pathway. J Immunol 1992;148:1993.

    PubMed  CAS  Google Scholar 

  56. Damle NK, Klussman K, Leytze G, Linsley PS: Proliferation of human T lymphocytes induced with superantigens is not dependent on costimulation by the CD28 counterreceptor B7. J Immunol 1993;150:726.

    PubMed  CAS  Google Scholar 

  57. Isobe M, Yagita H, Okumura K, Ihara A: Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science 1992;255:1125.

    Article  PubMed  CAS  Google Scholar 

  58. Davis LS, Kavanaugh AF, Nichols LA, Lipsky PE: Induction of persistent T cell hyporesponsiveness in vivo by monoclonal antibody to ICAM-1 in patients with rheumatoid arthritis. J Immunol 1995;154:3525.

    PubMed  CAS  Google Scholar 

  59. Sligh JJ, Ballantyne CM, Rich SS, Hawkins HK, Smith CW, Bradley A, Beaudet AL: Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci USA 1993;90:8529.

    Article  PubMed  CAS  Google Scholar 

  60. Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer TA, Gutierrez RJ: Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med 1994;180:95.

    Article  PubMed  CAS  Google Scholar 

  61. Croft M, Bradley LM, Swain SL: Naive versus memory CD4 T cell response to antigen: Memory cells are less dependent on accessory cell costimulation and can respond to many APC types including resting B cells. J Immunol 1994;152:2675.

    PubMed  CAS  Google Scholar 

  62. Sagerström CG, Kerr EM, Allison JP, Davis MM: Activation and differentiation requirements of primary T cells in vitro. Proc Natl Acad Sci 1993;90:8987.

    Article  PubMed  Google Scholar 

  63. McKnight AJ, Perez VL, Shea CM, Gray GS, Abbas AK: Costimulator dependence of lymphokine secretion by naive and activated CD4+ T lymphocytes from TCR transgenic mice. J Immunol 1994;152:5220.

    PubMed  CAS  Google Scholar 

  64. Byrne JA, Butler JL, Cooper MD: Differential activation requirements for virgin and memory T cells. J Immunol 1988;141:3249.

    PubMed  CAS  Google Scholar 

  65. Horgan KJ, Van Seventer GA, Shimizu Y, Shaw S: Hyporesponsiveness of ‘naive’ (CD45RA+) human T cells to multiple receptormediated stimuli but augmentation of response by costimuli. Eur J Immunol 1990;20:1111.

    Article  PubMed  CAS  Google Scholar 

  66. Luqman M, Bottomly K: Activation requirements for CD4+ T cells differing in CD45R expression. J Immunol 1992;149:2300.

    PubMed  CAS  Google Scholar 

  67. Liu Y, Jones B, Brady W, Janeway CA Jr, Linsley PS: Co-stimulation of murine CD4 T cell growth: Cooperation between B7 and heat-stable antigen. Eur J Immunol 1992;22:2855.

    Article  PubMed  CAS  Google Scholar 

  68. Parra E, Gjorloff Wingren A, Hedlund G, Bjorklund M, Sjogren H-O, Kalland T, Sansom D, Dohlsten M: Costimulation of human CD4+ T lymphocytes with B7 and lymphocyte function-associated antigen-3 results in distinct cell activation profiles. J Immunol 1994;153:2479.

    PubMed  CAS  Google Scholar 

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  1. Department of Biology, University of California San Diego, La Jolla, Calif., USA

    Caroline Dubey & Michael Croft

  2. INSERM U430, Hospital Broussais, Pavillon Leriche, 96, rue Didot, F-75014, Paris, (France)

    Caroline Dubey

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Dubey, C., Croft, M. Accessory molecule regulation of naive CD4 T cell activation. Immunol Res 15, 114–125 (1996). https://doi.org/10.1007/BF02918501

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