This article outlines my early start in medicine, a late start in immunology research, and my efforts to integrate the two activities. I first describe some of the background information, excitement, and implications of the recognition of T and B cells as separate but functionally intertwined arms of the adaptive immune system. The article continues with a brief account of my colleagues' and my efforts to use the model of hematopoietic stem cell differentiation along T and B cell lines to gain a better understanding of immunodeficiency diseases and lymphoid malignancies. It concludes with the discovery of a more ancient adaptive immune system in which T-like and B-like cells in jawless vertebrates use variable lymphocyte receptors constructed with leucine-rich-repeat sequences to recognize antigens.


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Literature Cited

  1. Burnet FM. 1.  1959. The Clonal Selection Theory of Acquired Immunity Nashville, TN: Vanderbilt Univ. Press [Google Scholar]
  2. Cooper MD, Lusher J. 2.  1964. Immunologic tolerance of ABO incompatible erythrocytes in human neonates. J. Pediatr. 65:831–38 [Google Scholar]
  3. West LJ. 3.  2004. Crossing the ABO barrier in infant heart transplantation at the Hospital for Sick Children. Clin. Transpl. 18:243–52 [Google Scholar]
  4. Miller JFAP. 4.  1961. The immunological function of the thymus. Lancet 2:748–49 [Google Scholar]
  5. Good RA, Dalmasso AP, Martinez C, Archer OK, Pierce JC. 5.  et al. 1962. The role of the thymus in development of immunologic capacity in rabbits and mice. J. Exp. Med. 116:773–76 [Google Scholar]
  6. Jankovic BD, Waksman BH, Arnason BG. 6.  1962. Role of the thymus in immune reactions in rats. J. Exp. Med. 116:159–76 [Google Scholar]
  7. Gowans JL, Knight EJ. 7.  1964. The route of recirculation of lymphocytes in the rat. Proc. R. Soc. London Ser. B Biol. Sci. 159:257–82 [Google Scholar]
  8. Porter RR. 8.  1959. The hydrolysis of rabbit γ-globulin and antibodies with crystalline papain. Biochem. J. 73:119–27 [Google Scholar]
  9. Edleman GM. 9.  1959. Dissociation of γ-globulin. J. Am. Chem. Soc. 81:3155–56 [Google Scholar]
  10. Peterson RDA, Burmester BR, Fredrickson TN, Purchase HG, Good RA. 10.  1964. Effect of bursectomy and thymectomy on the development of visceral lymphomatosis in the chicken. J. Natl. Cancer Inst. 32:1343–54 [Google Scholar]
  11. Peterson RDA, Purchase MG, Burmester BR, Cooper MD, Good RA. 11.  1966. Relationships among visceral lymphomatosis, bursa of Fabricius, and bursa-dependent lymphoid tissue of the chicken. J. Natl. Cancer Inst. 36:585–98 [Google Scholar]
  12. Landsteiner K, Chase MW. 12.  1942. Experiments on transfer of cutaneous sensitivity to simple compounds. Proc. Soc. Exp. Biol. Med. 49:688–90 [Google Scholar]
  13. Chase MW. 13.  1945. The cellular transfer of cutaneous hypersensitivity to tuberculin. Proc. Soc. Exp. Biol. Med. 59:134–35 [Google Scholar]
  14. Glick B, Chang TS, Jaap RG. 14.  1956. The bursa of Fabricius and antibody production. Poult. Sci. 35:224–25 [Google Scholar]
  15. Warner NL, Szenberg A, Burnet FM. 15.  1962. The immunological role of different lymphoid organs in the chicken. I. Dissociation of immunological responsiveness. Aust. J. Exp. Biol. Med. Sci. 40:373–87 [Google Scholar]
  16. Cooper MD, Chase HP, Lowman JT, Krivit W, Good RA. 16.  1968. Wiskott-Aldrich Syndrome. An immunologic deficiency disease involving the afferent limb of immunity. Am. J. Med. 44:499–513 [Google Scholar]
  17. Cooper MD, Peterson RDA, Good RA. 17.  1965. Delineation of the thymic and bursal lymphoid systems in the chicken. Nature 205:143–46 [Google Scholar]
  18. Cooper MD, Peterson RDA, South MA, Good RA. 18.  1966. The functions of the thymus system and the bursa system in the chicken. J. Exp. Med. 23:75–102 [Google Scholar]
  19. Becker AJ, McCulloch EA, Till JE. 19.  1963. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197:452–54 [Google Scholar]
  20. Ford CE, Micklem HS. 20.  1963. The thymus and lymph nodes in radiation chimaeras. Lancet 281:359–62 [Google Scholar]
  21. Moore MAS, Owen JJT. 21.  1967. Stem cell migration in developing myeloid and lymphoid systems. Lancet 290:658–59 [Google Scholar]
  22. Peterson RDA, Cooper MD, Good RA. 22.  1965. The pathogenesis of immunologic deficiency diseases. Am. J. Med. 38:579–604 [Google Scholar]
  23. Nezelof C, Jammet ML, Lertholary P, Labrune B, Lamy ML. 23.  1964. L'hypoplasie héréditaire du thymus: sa place et sa responsabilité dans une observation d'aplasie lymphocytaire normoplasmocytaire et normoglobulinémique du nourrison. Arch. Franc. Pediatr. 21:897 [Google Scholar]
  24. Cooper MD, Peterson RDA, Good RA. 24.  1965. A new concept of the cellular basis of immunity. (Discussion). J. Pediatr. 67:907–908 [Google Scholar]
  25. Roitt IM, Greaves MF, Torrigiani G, Brostoff J, Playfair JHL. 25.  1969. Cellular basis of immunological responses. Lancet 294:367–71 [Google Scholar]
  26. Clamen HN, Chaperon EA, Triplett RF. 26.  1966. Thymus-marrow cell combinations. Synergism in antibody production. Proc. Soc. Exp. Biol. Med. 122:1167–71 [Google Scholar]
  27. Mitchell GF, Miller JFAP. 27.  1968. Cell to cell interaction in the immune response. II. The source of homolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes. J. Exp. Med. 128:126–35 [Google Scholar]
  28. Mitchison NA. 28.  1971. The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation. Eur. J. Immunol. 1:18–27 [Google Scholar]
  29. Webb CS, Cooper MD. 29.  1973. T cells can bind antigen via cytophilic IgM antibody made by B cells. J. Immunol. 111:275–77 [Google Scholar]
  30. Zinkernagel RM, Doherty PC. 30.  1973. Cytotoxic thymus-derived lymphocytes in cerebrospinal fluid of mice with lymphocytic choriomeningitis. J. Exp. Med. 138:1266–69 [Google Scholar]
  31. Yanagi Y, Yoshikai Y, Leggett SP, Clark J, Aleksander I, Mak TW. 31.  1984. A human T cell specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308:145–49 [Google Scholar]
  32. Hedrick SM, Cohen DI, Nielsen EA, Davis MM. 32.  1984. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308:149–53 [Google Scholar]
  33. Bockman DE, Cooper MD. 33.  1973. Pinocytosis by epithelium associated with lymphoid follicles in the bursa of Fabricius, appendix, and Peyer's patches. Am. J. Anat. 136:455–78 [Google Scholar]
  34. Cooper MD, Cain WA, Van Alten PJ, Good RA. 34.  1969. Development and function of the immunoglobulin system. I. Effect of bursectomy at different stages of development on germinal centers, plasma cells, immunoglobulins and antibody production. Int. Arch. Allergy Appl. Immunol. 35:242–52 [Google Scholar]
  35. Kincade PW, Cooper MD. 35.  1971. Development and distribution of immunoglobulin-containing cells in the chicken. An immunofluorescent analysis using purified antibodies to μ, γ and light chains. J. Immunol. 106:371–82 [Google Scholar]
  36. Kincade PW, Cooper MD. 36.  1973. Immunoglobulin A. Site and sequence of expression in developing chicks. Science 179:398–400 [Google Scholar]
  37. Dray S. 37.  1962. Effect of maternal isoantibodies on the quantitative expression of two allelic genes controlling γ-globulin allotypic specificities. Nature 195:677–80 [Google Scholar]
  38. Kincade PW, Lawton AR, Bockman DE, Cooper MD. 38.  1970. Suppression of immunoglobulin G synthesis as a result of antibody-mediated suppression of immunoglobulin M synthesis in chickens. Proc. Natl. Acad. Sci. USA 67:1819–925 [Google Scholar]
  39. Lawton AR, Asofsky R, Hylton MB, Cooper MD. 39.  1972. Suppression of immunoglobulin class synthesis in mice. I. Effects of treatment with antibody to μ chain. J. Exp. Med. 135:277–97 [Google Scholar]
  40. Raff MC, Owen JJT, Cooper MD, Lawton AR III, Megson M, Gathings WE. 40.  1975. Differences in susceptibility of mature and immature mouse B lymphocytes to anti-immunoglobulin induced immunoglobulin suppression in vitro: possible implications for B cell tolerance to self. J. Exp. Med. 142:1052–64 [Google Scholar]
  41. Nossal JV, Pike BL. 41.  1975. Evidence for the clonal abortion theory of B lymphocyte tolerance. J. Exp. Med. 141:904–17 [Google Scholar]
  42. Goodnow CC. 42.  1996. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc. Natl. Acad. Sci. USA 93:2264–71 [Google Scholar]
  43. Tonegawa S. 43.  1983. Somatic generation of antibody diversity. Nature 302:571–81 [Google Scholar]
  44. Dryer WJ, Bennett JC. 44.  1965. The molecular basis of antibody formation: a paradox. Proc. Natl. Acad. Sci. USA 54:864–69 [Google Scholar]
  45. Cooper MD, Lawton AR. 45.  1974. The development of the immune system. Sci. Am. 231:58–72 [Google Scholar]
  46. Honjo T, Kinoshita K, Muramatsu M. 46.  2002. Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu. Rev. Immunol. 20:165–96 [Google Scholar]
  47. Sutherland DER, Archer OK, Good RA. 47.  1964. Role of the appendix in development of immunological capacity. Proc. Soc. Exp. Biol. Med. 115:673–76 [Google Scholar]
  48. Cooper MD, Perey DY, McKneally MF, Gabrielsen AE, Sutherland DER, Good RA. 48.  1966. A mammalian equivalent of the avian bursa of Fabricius. Lancet 287:1388–91 [Google Scholar]
  49. Cooper MD, Lawton AR. 49.  1972. The mammalian “bursa-equivalent”: Does lymphoid differentiation along plasma cell lines begin in the gut-associated lymphoepithelial tissues (GALT) of mammals?. Contemporary Topics in Immunobiology MG Hanna 49–68 New York: Plenum [Google Scholar]
  50. Owen JJT, Cooper MD, Raff MC. 50.  1974. In vitro generation of B lymphocytes in mouse fetal liver, a mammalian ‘bursa equivalent.’. Nature 249:361–63 [Google Scholar]
  51. Osmond DG, Nossal GJV. 51.  1974. Differentiation of lymphocytes in mouse bone marrow. II. Kinetics of maturation and renewal of antiglobulin-binding cells studied by double labeling. Cell. Immunol. 13:132–45 [Google Scholar]
  52. Ryser JE, Vassalli P. 52.  1974. Mouse bone marrow lymphocytes and their differentiation. J. Immunol. 113:719–28 [Google Scholar]
  53. Owen JJT, Raff MC, Cooper MD. 53.  1975. Studies on the generation of B lymphocytes in the mouse embryo. Eur. J. Immunol. 5:468–73 [Google Scholar]
  54. Raff MC, Megson M, Owen JJT, Cooper MD. 54.  1976. Early production of intracellular IgM by B lymphocyte precursors in mouse. Nature 259:224–26 [Google Scholar]
  55. Owen JJT, Wright DE, Habu S, Raff MC, Cooper MD. 55.  1977. Studies on the generation of B lymphocytes in fetal liver and bone marrow. J. Immunol. 118:2067–72 [Google Scholar]
  56. Gathings WE, Lawton AR, Cooper MD. 56.  1977. Immunofluorescent studies of the development of pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur. J. Immunol. 7:804–10 [Google Scholar]
  57. Burrows PD, Kearney JF, Lawton AR, Cooper MD. 57.  1978. Pre-B cells: bone marrow persistence in anti-μ suppressed mice, conversion to B lymphocytes, and recovery following destruction by cyclophosphamide. J. Immunol. 120:1526–31 [Google Scholar]
  58. Hayward AR, Simons MA, Lawton AR, Mage RG, Cooper MD. 58.  1978. Pre-B and B cells in rabbits: ontogeny and allelic exclusion of kappa light chain genes. J. Exp. Med. 148:1367–77 [Google Scholar]
  59. Burrows PD, LeJeune M, Kearney JF. 59.  1979. Evidence that murine pre-B cells synthesize μ heavy chains but no light chains. Nature. 280:838–41 [Google Scholar]
  60. Willerford DM, Swat W, Alt FW. 60.  1996. Developmental regulation of V(D)J recombination and lymphocyte differentiation. Curr. Opin. Genet. Dev. 6:603–9 [Google Scholar]
  61. Abney ER, Cooper MD, Kearney JF, Lawton AR, Parkhouse RME. 61.  1978. Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity. J. Immunol. 120:2041–49 [Google Scholar]
  62. Cooper MD, Lawton AR. 62.  1972. Circulating B-cells in patients with immunodeficiency. Am. J. Pathol. 69:513–27 [Google Scholar]
  63. Cooper MD, Lawton AR, Bockman DE. 63.  1971. Agammaglobulinemia with B lymphocyte: a specific defect of plasma cell differentiation. Lancet 298:791–95 [Google Scholar]
  64. Vogler LB, Pearl ER, Gathings WE, Lawton AR, Cooper MD. 64.  1976. B-lymphocyte precursors in the bone marrow of patients with immunoglobulin deficiency diseases. Lancet 308:376 [Google Scholar]
  65. Levitt D, Haber P, Rich K, Cooper MD. 65.  1983. Hyper IgM immunodeficiency: a primary dysfunction of B lymphocyte isotype switching. J. Clin. Investig. 72:1650–57 [Google Scholar]
  66. Conley ME, Cooper MD. 66.  1981. Immature phenotype of IgA cells in IgA deficient patients. N. Engl. J. Med. 305:495–97 [Google Scholar]
  67. Ochs HD, Smith CIE, Puck J. 67.  2007. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach New York: Oxford Univ. Press [Google Scholar]
  68. Cooper MD, Payne LN, Dent PB, Burmester BR, Good RA. 68.  1968. Pathogenesis of avian lymphoid leukosis. I. Histogenesis. J. Natl. Cancer Inst. 41:373–90 [Google Scholar]
  69. Thompson CB, Challoner PB, Neiman PE. 69.  1986. Normal and neoplastic B cell development in the bursa of fabricius. Curr. Top. Microbiol. Immunol. 132:209–14 [Google Scholar]
  70. Cairns J. 70.  1975. Mutation selection and the natural history of cancer. Nature 255:197–200 [Google Scholar]
  71. Vogler LB, Crist WM, Bockman DE, Pearl ER, Lawton AR, Cooper MD. 71.  1978. Pre-B cell leukemia: a new phenotype of childhood lymphoblastic leukemia. N. Engl. J. Med. 298:872–78 [Google Scholar]
  72. Vogler LB, Crist WM, Sarrif AM, Pullen DJ, Bartolucci AA. 72.  et al. 1981. An analysis of clinical and laboratory features of acute lymphocytic leukemias with emphasis on 35 children with pre-B leukemia. Blood 58:135–40 [Google Scholar]
  73. Volger LB, Crist WM, Vinson PC, Sarrif A, Brattain MG, Coleman MS. 73.  1979. Philadelphia chromosome pre-B leukemia presenting as blast crisis of chronic myelogenous leukemia. Blood 54:1164–70 [Google Scholar]
  74. Kubagawa H, Vogler LB, Capra JD, Conrad ME, Lawton AR, Cooper MD. 74.  1979. Studies on the clonal origin of multiple myeloma: use of individually specific (idiotype) antibodies to trace the oncogenic event to its earliest point of expression in B-cell differentiation. J. Exp. Med. 150:792–807 [Google Scholar]
  75. Mayumi M, Kubagawa H, Omura GA, Gathings WE, Kearney JF, Cooper MD. 75.  1982. Studies on the clonal origin of human B cell leukemia using monoclonal anti-idiotype antibodies. J. Immunol. 129:904–10 [Google Scholar]
  76. Bertoli LF, Kubagawa H, Borzillo GV, Burrows PD, Schreeder MT. 76.  et al. 1988. Bone marrow origin of a B cell lymphoma. Blood 72:94–101 [Google Scholar]
  77. Cooper MD, Chen CH, Bucy RP, Thompson CB. 77.  1991. Avian T cell ontogeny. Adv. Immunol. 50:87–117 [Google Scholar]
  78. Göbel TWF, Chen CH, Lahti J, Kubota T, Kuo C. 78.  et al. 1994. Identification of, T cell receptor alpha (TCRa) genes in the chicken. Proc. Natl. Acad. Sci. USA 91:1094–98 [Google Scholar]
  79. Kubota T, Wang J-Y, Gobel TWF, Hockett R, Cooper MD, Chen CH. 79.  1999. Characterization of an avian (Gallus gallus domesticus) TCR α/δ gene locus. J. Immunol. 163:3858–66 [Google Scholar]
  80. Coltey M, Bucy RP, Chen CH, Cihak J, Lösch U. 80.  et al. 1989. Analysis of the first two waves of thymus homing stem cells and their T cell progeny in chick-quail chimeras. J. Exp. Med. 170:543–57 [Google Scholar]
  81. Bucy RP, Chen CH, Cooper MD. 81.  1990. Ontogeny of T cell receptors in the chicken thymus. J. Immunol. 144:1161–68 [Google Scholar]
  82. Dunon D, Courtois D, Vainio O, Six A, Chen CH. 82.  et al. 1997. Ontogeny of the immune system: γ/δ and α/β T cells migrate from thymus to the periphery in alternating waves. J. Exp. Med. 186:977–88 [Google Scholar]
  83. Bucy RP, Chen CH, Cihak J, Lösch U, Cooper MD. 83.  1988. Avian T cells expressing γδ receptors localize in the splenic sinusoids and the intestinal epithelium. J. Immunol. 141:2200–5 [Google Scholar]
  84. Horton JD, Horton TL, Dzialo R, Gravenor I, Minter R. 84.  et al. 1998. T-cell and natural killer cell development in thymectomized Xenopus. Immunol. Rev. 166:245–58 [Google Scholar]
  85. Kong F-K, Chen CH, Cooper MD. 85.  1998. Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. Immunity 8:97–104 [Google Scholar]
  86. Kong F-K, Chen CH, Six A, Hockett RD, Cooper MD. 86.  1999. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl. Acad. Sci. USA 96:1536–40 [Google Scholar]
  87. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM. 87.  et al. 1998. Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–95 [Google Scholar]
  88. Patel DD, Gooding ME, Parrott RE, Curtis KM, Haynes BF, Buckley RH. 88.  2000. Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N. Engl. J. Med. 342:1325–32 [Google Scholar]
  89. Monteiro RC, Kubagawa H, Cooper MD. 89.  1990. Cellular distribution, regulation and biochemical nature of an Fcα receptor in humans. J. Exp. Med. 171:597–613 [Google Scholar]
  90. Kubagawa H, Burrows PD, Cooper MD. 90.  1997. A novel pair of immunoglobulin-like receptors expressed by B cells and myeloid cells. Proc. Natl. Acad. Sci. USA 94:5261–66 [Google Scholar]
  91. Dennis G Jr, Kubagawa H, Cooper MD. 91.  2000. Paired Ig-like receptor homologs in birds and mammals share a common ancestor with mammalian Fc receptors. Proc. Natl. Acad. Sci. USA 97:13245–50 [Google Scholar]
  92. Davis RS, Wang Y-H, Kubagawa H, Cooper MD. 92.  2001. Identification of a family of Fc receptor homologs with preferential B cell expression. Proc. Natl. Acad. Sci. USA 98:9772–77 [Google Scholar]
  93. Shintani S, Terzic J, Sato A, Saraga-Babic M, O'hUigin C. 93.  et al. 2000. Do lampreys have lymphocytes? The Spi evidence. Proc. Natl. Acad. Sci. USA 97:7417–22 [Google Scholar]
  94. Mayer WE, Uinuk-ool T, Tichy H, Gartland LA, Klein J, Cooper MD. 94.  2002. Isolation and characterization of lymphocyte-like cells from a lamprey. Proc. Natl. Acad. Sci. USA 99:14350–55 [Google Scholar]
  95. Uinuk-ool T, Sato A, Dongak R, Mayer WE, Cooper MD, Klein J. 95.  2002. Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc. Natl. Acad. Sci. USA 99:14356–61 [Google Scholar]
  96. Pancer Z, Amemiya CT, Ehrhardt GRA, Ceitlin J, Gartland GL, Cooper MD. 96.  2004. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430:174–80 [Google Scholar]
  97. Pancer Z, Kasahara M, Saha NR, Kasamatsu J, Amemiya CT, Cooper MD. 97.  2005. Variable lymphocyte receptors in hagfish. Proc. Natl. Acad. Sci. USA 102:9224–29 [Google Scholar]
  98. Rogozin IB, Iyer LM, Liang L, Glazko GV, Liston VG. 98.  et al. 2007. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat. Immunol. 8:647–56 [Google Scholar]
  99. Alder MN, Rogozin IB, Iyer LM, Glazko GV, Cooper MD, Pancer Z. 99.  2005. Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310:1970–73 [Google Scholar]
  100. Nagawa F, Kishishita N, Shimizu K, Hirose S, Miyoshi M, Nezu J. 100.  et al. 2007. Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nat. Immunol. 8:206–13 [Google Scholar]
  101. Guo P, Hirano M, Herrin BR, Li J, Yu C. 101.  et al. 2009. Dual nature of the adaptive immune system in lampreys. Nature 459:796–802 [Google Scholar]
  102. Herrin BR, Alder MN, Roux RH, Sina C, Ehrhardt GRA. 102.  et al. 2008. Structure and specificity of lamprey monoclonal antibodies. Proc. Natl. Acad. Sci. USA 105:2040–45 [Google Scholar]
  103. Han BW, Herrin BR, Cooper MD, Wilson IA. 103.  2008. Antigen recognition by variable lymphocyte receptors. Science 321:1834–37 [Google Scholar]
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