Journal of Clinical Immunology

, Volume 12, Issue 1, pp 1–10 | Cite as

Isoforms of the CD45 common leukocyte antigen family: Markers for human T-cell differentiation

  • Loran T. Clement
Special Article

Abstract

The diverse host defense and immunoregulatory functions of human T cells are performed by phenotypically heterogeneous subpopulations. Among the membrane antigens that are differentially expressed by reciprocal human T-cell subsets are the CD45RA and CD45RO isoforms of the common leukocyte antigen family, which have been hypothesized to identify “naive” and “memory” T cells, respectively. The CD45RA antigen is first expressed by T-lineage cells relatively late during their intrathymic maturation and continues to be expressed by most T cells in the immunologically naive neonate. With increasing age and antigenic exposure, however, CD45RA-/RO+ cells become more prevalent in the circulation and comprise the majority of cells in tissues. Analyses of the functional capabilities of CD4+CD45RA+ and CD4+CD45RO+ cells have shown that proliferative responses to “memory” recall antigens or the ability to provide help for antibody production are functions uniquely performed by CD4+CD45RA-/RO+ cells. The major immunoregulatory functions described for CD4+CD45RA+ cells involve suppression of immune responses, either directly or via the induction of suppressor activity by CD8+ cells. Two general models of differentiation have been proposed to describe the lineal relationship of these T-cell subsets. Although these subsets could represent mature, phenotypically and functionally stable progeny arising from separate differentiation pathways, there is considerable experimental support for the hypothesis that CD45RA-/RO+ cells are “memory” cells that derive from “naive” or “virgin” CD45RA+/RO-precursors via an activation-dependent postthymic differentiation pathway. Altered frequencies of CD45RA+ and CD45RO+ T cells have been observed in a variety of different clinical conditions, particularly diseases manifesting altered immune function. These findings have contributed new information concerning the physiological events regulating thein vivo generation of these T-cell subsets. In addition, they may provide clues to the pathogenetic processes associated with certain diseases.

Key words

Lymphocyte differentiation T-cell subpopulations CD45 isoforms common leukocyte antigens 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Pulido R, Sanchez-Madrid F: Biochemical nature and topographic localization of epitopes defining four distinct CD45 antigen specificities. Conventional CD45, CD45R, 180 kDa (UCHL1) and 220/205/190 kDa. J Immunol 143:1930–1936, 1989Google Scholar
  2. 2.
    Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H: Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens. J Exp Med 166:1548–1566, 1987Google Scholar
  3. 3.
    Tedder TF, Clement LT, Cooper MD: Human lymphocyte differentiation antigens HB-10 and HB-11. I. Ontogeny of antigen expression. J Immunol 134:2983–2988, 1985Google Scholar
  4. 4.
    Smith SH, Brown MH, Rowe D, Callard RE, Beverley PCL: Functional subsets of human helper-inducer cells defined by a new monoclonal antibody, UCHL1. Immunology 58:63–70, 1986Google Scholar
  5. 5.
    Pingel, JT, Thomas ML: Evidence that the leukocytecommon antigen is required for antigen-induced T lymphocyte proliferation. Cell 58:1055–1065, 1989Google Scholar
  6. 6.
    Schraven B, Roux M, Hutmacher B, Meuer SC: Triggering of the alternative pathway of human T cell activation involves members of the T200 family of glycoproteins. Eur J Immunol 19:397–403, 1989Google Scholar
  7. 7.
    Martorell J, Vilella R, Borche L, Rojo I, Vives J: A second signal for T cell mitogenesis provided by monoclonal antibodies CD45 (T200). Eur J Immunol 17:1447–1451, 1987Google Scholar
  8. 8.
    Ledbetter JA, Rose LM, Spooner CE, Beatty PG, Martin PJ, Clark EA: Antibodies to common leukocyte antigen p220 influence human T cell proliferation by modifying IL-2 receptor expression. J Immunol 135:1819–1828, 1985Google Scholar
  9. 9.
    Tonks NK, Charbonneau H, Diltz CD, Fischer EH, Walsh KA: Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. Biochemistry 27:8695–8704, 1988Google Scholar
  10. 10.
    Schraven B, Samstag Y, Altevogt P, Meuer S: Association of CD2 and CD45 on human T lymphocytes. Nature 345:71–74, 1990Google Scholar
  11. 11.
    Volarevic S, Burns CM, Sussman JJ, Ashwell JD: Intimate association of Thy-1 and the T-cell antigen receptor with the CD45 tyrosine phosphatase. Proc Natl Acad Sci USA 87:7085–7092, 1990Google Scholar
  12. 12.
    Kiener PA, Mittler RS: CD45-protein tyrosine phosphatase cross-linking inhibits T cell receptor CD3-mediated activation in human T cells. J Immunol 143:23–30, 1989Google Scholar
  13. 13.
    Ledbetter JA, Tonks NK, Fisher EH, Clark EA: CD45 regulates signal transduction and lymphocyte activation by specific association with receptor molecules on T or B cells. Proc Natl Acad Sci USA 85:8628–8634, 1988Google Scholar
  14. 14.
    Mustelin T, Coggeshall KM, Altman A: Rapid activation of the T-cell tyrosine protein kinase pp56lck by the CD45 phophotyrosine phosphatase. Proc Natl Acad Sci USA 86:6302–6308, 1989Google Scholar
  15. 15.
    Janossy G, Bofill M, Rowe D, Muir J, Beverley PCL: The tissue distribution of T lymphocytes expressing different CD45 polypeptides. Immunology 66:517–525, 1989Google Scholar
  16. 16.
    Gillitzer R, Pilarski LM: In situ localization of CD45 isoforms in the human thymus indicates a medullary location for the thymic generative lineage. J Immunol 144:66–74, 1990Google Scholar
  17. 17.
    Pilarski LM, Deans JP: Selective expression of CD45 isoforms and of maturation antigens during human thymocyte differentiation: Observations and hypothesis. Immunol Lett 21:187–198, 1989Google Scholar
  18. 18.
    Uittenbogaart C, Higashitani S, Scmid I, Boone T, Clement LT: Interleukin-4 induces expression of the CD45RA antigen on human thymocyte subpopulations. Intl Immunol 2:1179–1187, 1990Google Scholar
  19. 19.
    Merkenschlager M, Fisher AG: CD45 isoform switching precedes the activation-driven death of human thymocytes by apoptosis. Intl Immunol 3:1–7, 1991Google Scholar
  20. 20.
    Pilarski LM, Gillitzer R, Zola H, Shortman K, Scollary R: Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200). Eur J Immunol 19:589–597, 1989Google Scholar
  21. 21.
    Paoli PD, Battistin S, Santini GF: Age-related changes in human lymphocyte subsets: Progressive reduction of the CD4 CD45R (suppressor inducer) population. Clin Immunol Immunopathol 48:290–296, 1988Google Scholar
  22. 22.
    Morimoto C, Letvin NL, Distaso JA, Aldrich WR, Schlossman SF: The isolation and characterization of the human suppressor inducer T cell subset. J Immunol 134:1508–1513, 1985Google Scholar
  23. 23.
    Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, Kapsenberg ML: Predominance of “memory” T cells (CD4+, CD29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased skin. Arch Dermatol 281:24–32, 1989Google Scholar
  24. 24.
    Harvey J, Jones DB, Wright DH: Leucocyte common antigen expression on T cells in normal and inflamed human gut. Immunology 68:13–17, 1989Google Scholar
  25. 25.
    Merkenschlager M, Terry W, Edwards R, Beverley PCL: Limiting dilution analysis of proliferative responses in human lymphocyte populations defined by the monoclonal antibody UCHL1: implications for differential CD45 expression in T cell memory formation. Eur J Immunol 18:1653–1661, 1988Google Scholar
  26. 26.
    Winterrowd GE, Sanders ME: Human memory and naive T lymphocytes have differential response to interleukin-1, interleukin-2, and interleukin-4. Clin Res 37:422A, 1989Google Scholar
  27. 27.
    Wasik MA, Morimoto C: Differential effects of cytokines on proliferative response of human CD4+ T lymphocytes subsets stimulated via T cell receptor complex. J Immunol 144:3334–3340, 1990Google Scholar
  28. 28.
    Byrne JA, Butler JL, Cooper MD: Differential activation requirements for virgin and memory T cells. J Immunol 141:3249–3257, 1988Google Scholar
  29. 29.
    Sanders ME, Makgoba MW, June CH, Young HA, Shaw S: Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation. Eur J Immunol 19:803–808, 1989Google Scholar
  30. 30.
    Matsuyama T, Anderson P, Daley JF, Schlossman S, Morimoto C: CD4+CD45RA cells are preferentially activated through the CD2 pathway. Eur J Immunol 18:1473–1476, 1988Google Scholar
  31. 31.
    Anderson P, Morimoto C, Breitmeyer JB, Schlossman SF: Regulatory interactions between members of the immunoglobulin superfamily. Immunol Today 9:199–203, 1988Google Scholar
  32. 32.
    de Jong R, Brouwer M, Miedema F, van Lier RAW: Human CD8+ T lymphocytes can be divided into CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation. J Immunol 146:2088–2094, 1991Google Scholar
  33. 33.
    Byrne JA, Butler JL, Reinherz EL, Cooper MD: Virgin and memory T cells have different requirements for activation via the CD2 molecule. Int Immunol 1:29–36, 1989Google Scholar
  34. 34.
    Tedder TF, Cooper MD, Clement LT: Human lymphocyte differentiation antigens HB-10 and HB-11. II. Differential production of B cell growth and differentiation factors by distinct helper T cell subpopulations. J Immunol 134:2989–2994, 1985Google Scholar
  35. 35.
    Sleasman JW, Morimoto C, Schlossman S, Tedder TF: The role of functionally distinct helper T lymphocyte subpopulations in the induction of human B cell differentiation. Eur J Immunol 20:1357–1366, 1990Google Scholar
  36. 36.
    Yamashita N, Bullington R, Clement LT: Equivalent helper functions of human “naive” and “memory” CD4+ T cells for the generation of alloreactive cytotoxic T lymphocytes. J Clin Immunol 10:237–246, 1990Google Scholar
  37. 37.
    Kalish RS, Morimoto C, Schlossman SF. Generation of CD8 (T8) cytotoxic cells has a preferential requirement for CD4+2H4− inducer cells. Cell Immunol 111:379–385, 1988Google Scholar
  38. 38.
    Takeuchi T, Rudd CE, Schlossman SF, Morimoto C: Induction of suppression following autologous mixed lymphocyte reaction: Role of a novel 2H4 antigen. Eur J Immunol 17:97–104, 1987Google Scholar
  39. 39.
    Takeuchi T, Rudd CE, Tanaka S, Rothstein DM, Schlossman SF, Morimoto C: Functional characterization of the CD45R(2H4) molecule on CD8(T8) cells in the AMLR system. Eur J Immunol 19:747–752, 1989Google Scholar
  40. 40.
    Damle NK, Childs AL, Doyle LV: Immunoregulatory T lymphocytes in man: Soluble antigen-specific suppressor-inducer T lymphocytes are derived from the CD4+CD45R-p80+ subpopulation. J Immunol 139:1501–1508, 1987Google Scholar
  41. 41.
    Hirohata S, Lipsky PE: T cell regulation of human B cell proliferation and differentiation. Regulatory influences of CD45R+ and CD45R− T4 cell subsets. J Immunol 142:2597–2604, 1989Google Scholar
  42. 42.
    Moore K, Nesbitt AM: Identification and isolation of OKT4+ suppressor cells with the monoclonal antibody WR16. Immunology 58:659–667, 1986Google Scholar
  43. 43.
    Jacoby DR, Oldstone MBA: Delineation of suppressor and helper activity within the OKT4-defined T lymphocyte subset in human newborns. J Immunol 131:1765–1770, 1983Google Scholar
  44. 44.
    Clement LT, Vink PE, Bradley GB: Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate. J Immunol 145:102–108, 1990Google Scholar
  45. 45.
    Yamashita N, Clement LT: Phenotypic characterization of the post-thymic differentiation of human alloantigen-specific CD8+ cytotoxic T lymphocytes. J Immunol 143:1518–1523, 1989Google Scholar
  46. 46.
    Akbar AN, Salmon M, Janossy G: The synergy between naive and memory T cells during activation. Immunol Today 12:184–188, 1991Google Scholar
  47. 47.
    Sohen S, Rothstein DM, Tallman T, Gaudette D, Schlossman SF, Morimoto C: The functional heterogeneity of CD8+ cells defined by anti-CD45RA (2H4) and anti-CD29 (4B4) antibodies. Cell Immunol 128:314–328, 1990Google Scholar
  48. 48.
    Street NE, Mosmann TR: Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J 5:171–177, 1991Google Scholar
  49. 49.
    Lewis DB, Prickett KS, Larsen A, Grabstein K, Weaver M, Wilson CB: Restricted production of interleukin 4 by activated human T cells. Proc Natl Acad Sci USA 85:9743–9747, 1988Google Scholar
  50. 50.
    Dohlsten M, Hedlund G, Sjogren H-O, Carlsson R: Two subsets of human CD4+ T helper cells differing in kinetics and capacities to produce interleukin 2 and interferon-τ can be defined by the Leu-18 and UCHL1 monoclonal antibodies. Eur J Immunol 18:1173–1178, 1988Google Scholar
  51. 51.
    Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S: Human memory lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-τ production. J Immunol 140:1401–1408, 1988Google Scholar
  52. 52.
    Salmon M, Kitas GD, Bacon PA: Production of lymphokine mRNA by CD45R+ and CD45R− helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol 143:907–912, 1989Google Scholar
  53. 53.
    Morimoto C, Letvin NL, Boyd AW, Hagan M, Brown HM, Kornacki MA, Schlossman SF: The isolation and characterization of the human helper inducer T subset. J Immunol 134:3762–3771, 1985Google Scholar
  54. 54.
    Mackay CR: T-cell memory: The connection between function, phenotype, and migration pathways. Immunol Today 12:189–193, 1991Google Scholar
  55. 55.
    Camerini D, James SP, Stamenkovic I, Seed B: Leu-8/TQ1 is the human equivalent of the Mel-14 lymph node homing receptor. Nature 342:78–82, 1989Google Scholar
  56. 56.
    Sanders ME, Makgoba MW, Shaw S: Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today 9:195–199, 1988Google Scholar
  57. 57.
    Serra HM, Krowka JF, Ledbetter JA, Pilarski LM: Loss of CD45R (Lp220) represents a post-thymic T cell differentiation event. J Immunol 140:1441–1445, 1988Google Scholar
  58. 58.
    Akbar AN, Terry L, Timms A, Beverley PCL, Janossy G: Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 140:2171–2176, 1988Google Scholar
  59. 59.
    Clement LT, Yamashita N, Martin AM: The functionally distinct subpopulations of human helper/inducer T lymphocytes defined by anti-CD45R antibodies derive sequentially from a differentiation pathway that is regulated by activation-dependent post-thymic differentiation. J Immunol 141:1464–1470, 1988Google Scholar
  60. 60.
    Powrie F, Mason D: The MRC OX-22- CD4+ T cells that help B cells in secondary immune responses derive from naive precursors with the MRC OX-22+ CD4+ phenotype. J Exp Med 169:653–662, 1989Google Scholar
  61. 61.
    Deans JP, Boyd AW, Pilarski LM: Transition from high to low molecular weight isoforms of CD45 (T200) involve a rapid activation of alternate mRNA splicing and slow turnover of surface CD45R. J Immunol 143:1233–1238, 1989Google Scholar
  62. 62.
    Reimhold U, Pawelec G, Fratila A, Leippold S, Bauer R, Kreyssel HW: Phenotypic and functional characterization of tumor infiltrating lymphocytes in mycosis fungoides: Continuous growth of CD4+CD45R+ T cell clones with suppressor-inducer activity. J Invest Dermatol 94:304–3089, 1990Google Scholar
  63. 63.
    Rothstein DM, Sohen S, Daley JF, Schlossman SF, Morimoto C: CD4+CD45RA+ and CD4+CD45R− T cell subsets in man maintain distinct function and CD45RA expression persists on a subpopulation of CD45RA+ cells after activation with con A. Cell Immunol 129:449–467, 1990Google Scholar
  64. 64.
    Brod SA, Rudd CE, Purvee M, Hafler DA: Lymphokine regulation of CD45R expression on human T cell clones. J Exp Med 170:2147–2151, 1989Google Scholar
  65. 65.
    Rothstein DM, Yamada A, Schlossman SF, Morimoto C: Cyclic regulation of CD45 isoform expression in a long-term human CD4+CD45RA+ T cell line. J Immunol 146:1175–1182, 1991Google Scholar
  66. 66.
    Bell EB, Sparshott SM: Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 348:163–167, 1990Google Scholar
  67. 67.
    Rose LM, Ginsberg AH, Rothstein DL, Ledbetter JA, Clark EA: Selective loss of a subset of T helper cells in active multiple sclerosis. Proc Natl Acad Sci USA 82:7389–7394, 1985Google Scholar
  68. 68.
    Morimoto C, Hafler DA, Weiner DL, Letvin NL, Hagan M, Daley J, Schlossman SF: Selective loss of the suppressor-inducer T-cell subset in progressive multiple sclerosis: Analysis with anti-2H4 monoclonal antibody. N Engl J Med 16:67–71, 1987Google Scholar
  69. 69.
    Sobel RA, Hafler DA, Castro EE, Morimoto C, Weiner HL: The 2H4 (CD45R) antigen is selectively decreased in multiple sclerosis lesions. J Immunol 140:2210–2214, 1988Google Scholar
  70. 70.
    Morimoto C, Steinberg AD, Letvin NL, Hagen M, Takeuchi T, Daley J, Levine H, Schlossman SF: A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest 79:762–770, 1987Google Scholar
  71. 71.
    Emery P, Gentry KC, Mackay IR, Muirden KD, Rowley M: Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis. Arth Rheum 30:849–856, 1987Google Scholar
  72. 72.
    Pitzalis C, Kingsley G, Murphy J, Panayi G: Abnormal distribution of the helper-inducer and suppressor-inducer T lymphocyte subsets in the rheumatoid joint. Clin Immunol Immunopathol 45:252–258, 1987Google Scholar
  73. 73.
    Koch AE, Robinson PG, Radosevich JA, Pope RM: Distribution of CD45RA and CD45RO T lymphocyte subset in rheumatoid arthritis synovial tissue. J Clin Immunol 10:192–196, 1990Google Scholar
  74. 74.
    Rose NL, Ledbetter JA, Ginsberg AH, Clark EA, Rothstein TL: Suppressor-inducer cells in multiple sclerosis. N Engl J Med 317:118–123, 1987Google Scholar
  75. 75.
    Pitzalis C, Kingsley G, Haskard D, Panayi G: The preferential accumulation of helper-inducer T lymphocytes in inflamatory lesions; Evidence for regulation by selective endothelial and homotypic adhesion. Eur J Immunol 18:1398–1404, 1988Google Scholar
  76. 76.
    LeBranchu Y, Thibault G, Degenne D, Bardos P: Deficiency of CD4+CD45R+ T lymphocytes in common variable immunodeficiency. N Engl J Med 323:276–277, 1990Google Scholar
  77. 77.
    Tedder TF, Crain MJ, Kubagawa H, Clement LT, Cooper MD: Evaluation of lymphocyte differentiation in primary and secondary immunodeficiency diseases. J Immunol 135:1786–1791, 1985Google Scholar
  78. 78.
    Clement LT, Giorgi JV, Plaeger-Marshall S, Haas A, Stiehm ER, Martin AM: Abnormal differentiation of immunoregulatory T lymphocyte subpopulations in the major histocompatibility complex (MHC) class II antigen deficiency syndrome. J Clin Immunol 8:503–512, 1988Google Scholar
  79. 79.
    Clement LT, Plaeger-Marshall S, Haas A, Saxon A, Martin AM: Bare lymphocyte syndrome: Consequences of absent class II major histocompatibility antigen expression for B lymphocyte differentiation and function. J Clin Invest 81:669–675, 1988Google Scholar
  80. 80.
    Giorgi JV, Detels R: Subset alteration in HIV-infected homosexual men—NIAID Multicenter AIDS Cohort study. Clin Immunol Immunopathol 52:10–18, 1989Google Scholar
  81. 81.
    Schnittman SM, Lane HC, Greenhouse J: Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: Evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc Natl Acad Sci USA 87:6058–6062, 1990Google Scholar
  82. 82.
    Schwinzer R, Wonigeit, K: Genetically determined lack of CD45R− T cells in healthy individuals. Evidence for a regulatory polymorphisms of CD45R antigen expression. J Exp Med 171:1803–1808, 1990Google Scholar
  83. 83.
    Clement LT, Isacescu I, Champlin R, Giorgi JV, Bradley G: Differentiation of CD4+ T cell subpopulations after allogeneic bone marrow transplantation. Clin Res 38:432A, 1990Google Scholar
  84. 84.
    Hayward AR, Schiff S, Buckley RH: T cell reconstitution of SCID recipients grafted with T-depleted bone marrow.In Progress in Immune Deficiency III: Royal Society of Medicine Services International Congress and Symposium Series 173, JM Chapel, RJ Levinsky, ADB Webster (eds). London, Royal Society of Medicine Service, 1991, pp 174–175Google Scholar

Copyright information

© Plenum Publishing Corporation 1992

Authors and Affiliations

  • Loran T. Clement
    • 1
  1. 1.Department of PediatricsUCLA School of MedicineLos Angeles

Personalised recommendations