Skip to main content

Advertisement

Springer Nature Link
Log in

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

  • Special Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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, 1989

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1986

    Google Scholar 

  5. Pingel, JT, Thomas ML: Evidence that the leukocytecommon antigen is required for antigen-induced T lymphocyte proliferation. Cell 58:1055–1065, 1989

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1988

    Google Scholar 

  10. Schraven B, Samstag Y, Altevogt P, Meuer S: Association of CD2 and CD45 on human T lymphocytes. Nature 345:71–74, 1990

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1990

    Google Scholar 

  19. Merkenschlager M, Fisher AG: CD45 isoform switching precedes the activation-driven death of human thymocytes by apoptosis. Intl Immunol 3:1–7, 1991

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1989

    Google Scholar 

  24. Harvey J, Jones DB, Wright DH: Leucocyte common antigen expression on T cells in normal and inflamed human gut. Immunology 68:13–17, 1989

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1990

    Google Scholar 

  28. Byrne JA, Butler JL, Cooper MD: Differential activation requirements for virgin and memory T cells. J Immunol 141:3249–3257, 1988

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1988

    Google Scholar 

  31. Anderson P, Morimoto C, Breitmeyer JB, Schlossman SF: Regulatory interactions between members of the immunoglobulin superfamily. Immunol Today 9:199–203, 1988

    Google Scholar 

  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, 1991

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1989

    Google Scholar 

  42. Moore K, Nesbitt AM: Identification and isolation of OKT4+ suppressor cells with the monoclonal antibody WR16. Immunology 58:659–667, 1986

    Google Scholar 

  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, 1983

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1989

    Google Scholar 

  46. Akbar AN, Salmon M, Janossy G: The synergy between naive and memory T cells during activation. Immunol Today 12:184–188, 1991

    Google Scholar 

  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, 1990

    Google Scholar 

  48. Street NE, Mosmann TR: Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J 5:171–177, 1991

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1985

    Google Scholar 

  54. Mackay CR: T-cell memory: The connection between function, phenotype, and migration pathways. Immunol Today 12:189–193, 1991

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1989

    Google Scholar 

  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, 1991

    Google Scholar 

  66. Bell EB, Sparshott SM: Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 348:163–167, 1990

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1987

    Google Scholar 

  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, 1990

    Google Scholar 

  74. Rose NL, Ledbetter JA, Ginsberg AH, Clark EA, Rothstein TL: Suppressor-inducer cells in multiple sclerosis. N Engl J Med 317:118–123, 1987

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1985

    Google Scholar 

  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, 1988

    Google Scholar 

  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, 1988

    Google Scholar 

  80. Giorgi JV, Detels R: Subset alteration in HIV-infected homosexual men—NIAID Multicenter AIDS Cohort study. Clin Immunol Immunopathol 52:10–18, 1989

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1990

    Google Scholar 

  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, 1990

    Google Scholar 

  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 174–175

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, UCLA School of Medicine, 90024, Los Angeles, California

    Loran T. Clement

Authors
  1. Loran T. Clement
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clement, L.T. Isoforms of the CD45 common leukocyte antigen family: Markers for human T-cell differentiation. J Clin Immunol 12, 1–10 (1992). https://doi.org/10.1007/BF00918266

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00918266

Key words

Search

Navigation