CD4/CD8 coreceptors in thymocyte development, selection, and lineage commitment: Analysis of the CD4/CD8 lineage decision

Advances in Immunology

Volumn 83, Issue , 2004, Pages 91-131

  Singer, Alfred ^a   Bosselut, Remy ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; CYTOKINE RECEPTOR; INTERLEUKIN 7; INTERLEUKIN 7 RECEPTOR; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PROTEIN BCL 2; PROTEIN KINASE FYN; PROTEIN KINASE LCK; PROTEIN KINASE ZAP 70; PROTEIN TYROSINE KINASE; T LYMPHOCYTE RECEPTOR;

ANTIGEN BINDING; ANTIGEN SPECIFICITY; B LYMPHOCYTE DIFFERENTIATION; BINDING AFFINITY; CELL FATE; CELL LINEAGE; CELL MATURATION; CELL SELECTION; CELL TYPE; CELLULAR IMMUNITY; COMPLEX FORMATION; ENZYME ACTIVITY; GENE EXPRESSION; GENE LOCUS; GENE REARRANGEMENT; GENE SILENCING; GENETIC TRANSCRIPTION; HUMAN; IMMUNE SYSTEM; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE SUBPOPULATION; MAJOR HISTOCOMPATIBILITY COMPLEX RESTRICTION; NONHUMAN; PRIORITY JOURNAL; PROGENY; PROMOTER REGION; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; RECEPTOR INTRINSIC ACTIVITY; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE RECEPTOR GENE; THYMOCYTE; UPREGULATION;

EID: 2442708080     PISSN: 00652776     EISSN: None     Source Type: Book Series    
DOI: 10.1016/S0065-2776(04)83003-7     Document Type: Article

References (181)

1. Aifantis, I., Borowski, C., Gounari, F., Lacorazza, H. D., Nikolich-Zugich, J., and von Boehmer, H. (2002). A critical role for the cytoplasmic tail of pTalpha in T lymphocyte development. Nat. Immunol. 3, 483-488.
2. Aifantis, I., Gounari, F., Scorrano, L., Borowski, C., and von Boehmer, H. (2001). Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-kappaB and NFAT. Nat. Immunol. 2, 403-409.
3. Allman, D., Karnell, F. G., Punt, J. A., Bakkour, S., Xu, L., Myung, P., Koretzky, G. A., Pui, J. C., Aster, J. C., and Pear, W. S. (2001). Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J. Exp. Med. 194, 99-106.
4. Ardouin, L., Boyer, C., Gillet, A., Trucy, J., Bernard, A. M., Nunes, J., Delon, J., Trautmann, A., He, H. T., Malissen, B., and Malissen, M. (1999). Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling. Immunity 10, 409-420.
5. Ashton-Rickardt, P. G., Bandeira, A., Delaney, J. R., Van, K. L., Pircher, H. P., Zinkernagel, R. M., and Tonegawa, S. (1994). Evidence for a differential avidity model of T cell selection in the thymus. Cell 76, 651-663.
6. Baron, A., Hafen, K., and von Boehmer, H. (1994). A human CD4 transgene rescues CD4-CD8+ cells in beta 2-microglobulin-deficient mice. Eur. J. Immunol. 24, 1933-1936.
7. Barthlott, T., Kohler, H., and Eichmann, K. (1997a). Asynchronous coreceptor downregulation after positive thymic selection: Prolonged maintenance of the double positive state in CD8 lineage differentiation due to sustained biosynthesis of the CD4 coreceptor. J. Exp. Med. 185, 357-362.
8. Barthlott, T., Kohler, H., Pircher, H., and Eichmann, K. (1997b). Differentiation of CD4(high)CD8(low) coreceptor-skewed thymocytes into mature CD8 single-positive cells independent of MHC class I recognition. Eur. J. Immunol. 27, 2024-2032.
9. Bendelac, A., Killeen, N., Littman, D. R., and Schwartz, R. H. (1994). A subset of CD4+ thymocytes selected by MHC class I molecules. Science 263, 1774-1778.
10. Bendelac, A., Rivera, M. N., Park, S. H., and Roark, J. H. (1997). Mouse CD1-specific NK1 T cells: Development, specificity, and function. Annu. Rev. Immunol. 15, 535-562.
11. Benveniste, P., Knowles, G., and Cohen, A. (1996). CD8/CD4 lineage commitment occurs by an instructional/default process followed by positive selection. Eur. J. Immunol. 26, 461-471.
12. Bhandoola, A., Cibotti, R., Punt, J. A., Granger, L., Adams, A. J., Sharrow, S. O., and Singer, A. (1999). Positive selection as a developmental progression initiated by alpha beta TCR signals that fix TCR specificity prior to lineage commitment. Immunity 10, 301-311.
13. Blanc, D., Bron, C., Gabert, J., Letourneur, F., MacDonald, H. R., and Malissen, B. (1988). Gene transfer of the Ly-3 chain gene of the mouse CD8 molecular complex: Co-transfer with the Ly-2 polypeptide gene results in detectable cell surface expression of the Ly-3 antigenic determinants. Eur. J. Immunol. 18, 613-619.
14. Bommhardt, U., Basson, M. A., Krummrei, U., and Zamoyska, R. (1999). Activation of the extracellular signal-related kinase/mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus. J. Immunol. 163, 715-722.
15. Bommhardt, U., Cole, M. S., Tso, J. Y., and Zamoyska, R. (1997). Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus. Eur. J. Immunol. 27, 1152-1163.
16. Bonifacino, J. S., McCarthy, S. A., Maguire, J. E., Nakayama, T., Singer, D. S., Klausner, R. D., and Singer, A. (1990). Novel post-translational regulation of TCR expression in CD4+CD8+ thymocytes influenced by CD4. Nature 344, 247-251.
17. Bonneville, M., Ishida, I., Mombaerts, P., Katsuki, M., Verbeek, S., Berns, A., and Tonegawa, S. (1989). Blockage of alpha beta T-cell development by TCR gamma delta transgenes. Nature 342, 931-934.
18. Bosselut, R., Feigenbaum, L., Sharrow, S. O., and Singer, A. (2001). Strength of signaling by CD4 and CD8 coreceptor tails determines the number but not the lineage direction of positively selected thymocytes. Immunity 14, 483-494.
19. Bosselut, R., Guinter, T. I., Sharrow, S. O., and Singer, A. (2003). Unravelling a revealing paradox: Why MHC-I signaled thymocytes "paradoxically" appear as CD4+81o transitional cells during positive selection of CD8+ T cells. J. Exp. Med. 197, 1709-1719.
20. Bosselut, R., Kubo, S., Guinter, T., Kopacz, J. L., Altman, J. D., Feigenbaum, L., and Singer, A. (2000). Role of CD8beta domains in CD8 coreceptor function: Importance for MHC I binding, signaling, and positive selection of CD8+ T cells in the thymus. Immunity 12, 409-418.
21. Bosselut, R., Zhang, W., Ashe, J. M., Kopacz, J. L., Samelson, L. E., and Singer, A. (1999). Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction. J. Exp. Med. 190, 1517-1526.
22. Brandle, D., Muller, C., Rulicke, T., Hengartner, H., and Pircher, H. (1992). Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc. Natl. Acad. Sci. USA 89, 9529-9533.
23. Brugnera, E., Bhandoola, A., Cibotti, R., Yu, Q., Guinter, T. I., Yamashita, Y., Sharrow, S. O., and Singer, A. (2000). Coreceptor reversal in the thymus: Signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 13, 59-71.
24. Buch, T., Rieux-Laucat, F., Forster, I., and Rajewsky, K. (2002). Failure of HY-specific thymocytes to escape negative selection by receptor editing. Immunity 16, 707-718.
25. Cardell, S., Tangri, S., Chan, S., Kronenberg, M., Benoist, C., and Mathis, D. (1995). CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J. Exp. Med. 182, 993-1004.
26. Chan, S. H., Cosgrove, D., Waltzinger, C., Benoist, C., and Mathis, D. (1993). Another view of the selective model of thymocyte selection. Cell 73, 225-236.
27. Chan, S. H., Waltzinger, C., Baron, A., Benoist, C., and Mathis, D. (1994). Role of coreceptors in positive selection and lineage commitment. EMBO J. 13, 4482-4489.
28. Cibotti, R., Bhandoola, A., Guinter, T. I., Sharrow, S. O., and Singer, A. (2000). CD8 coreceptor extinction in signaled CD4(+)CD8(+) thymocytes: Coordinate roles for both transcriptional and posttranscriptional regulatory mechanisms in developing thymocytes. Mol. Cell. Biol. 20, 3852-3859.
29. Cibotti, R., Punt, J. A., Dash, K. S., Sharrow, S. O., and Singer, A. (1997). Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals. Immunity 6, 245-255.
30. Corbella, P., Moskophidis, D., Spanopoulou, E., Mamalaki, C., Tolaini, M., Itano, A., Lans, D., Baltimore, D., Robey, E., and Kioussis, D. (1994). Functional commitment to helper T cell lineage precedes positive selection and is independent of T cell receptor MHC specificity. Immunity 1, 269-276.
31. Correia-Neves, M., Waltzinger, C., Mathis, D., and Benoist, C. (2001). The shaping of the T cell repertoire. Immunity 14, 21-32.
32. Cosgrove, D., Gray, D., Dierich, A., Kaufman, J., Lemeur, M., Benoist, C., and Mathis, D. (1991). Mice lacking MHC class II molecules. Cell 66, 1051-1066.
33. Crump, A. L., Grusby, M. J., Glimcher, L. H., and Cantor, H. (1993). Thymocyte development in major histocompatibility complex-deficient mice: Evidence for stochastic commitment to the CD4 and CD8 lineages. Proc. Natl. Acad. Sci. USA 90, 10739-10743.
34. Dave, V. P., Allman, D., Wiest, D. L., and Kappes, D. J. (1999). Limiting TCR expression leads to quantitative but not qualitative changes in thymic selection. J. Immunol. 162, 5764-5774.
35. Davey, G. M., Schober, S. L., Endrizzi, B. T., Dutcher, A. K., Jameson, S. C., and Hogquist, K. A. (1998). Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867-1874.
36. Davis, C. B., and Littman, D. R. (1994). Thymocyte lineage commitment: Is it instructed or stochastic? Curr. Opin. Immunol. 6, 266-272.
37. Davis, C. B., Killeen, N., Crooks, M. E., Raulet, D., and Littman, D. R. (1993). Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73, 237-247.
38. Dembic, Z., Haas, W., Zamoyska, R., Parnes, J., Steinmetz, M., and von Boehmer, H. (1987). Transfection of the CD8 gene enhances T-cell recognition. Nature 326, 510-511.
39. Devine, L., Kieffer, L. J., Aitken, V., and Kavathas, P. B. (2000). Human CD8 beta, but not mouse CD8 beta, can be expressed in the absence of CD8 alpha as a beta homodimer. J. Immunol. 164, 833-838.
40. Doyle, C., and Strominger, J. L. (1987). Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330, 256-259.
41. Dutz, J. P., Ong, C. J., Marth, J., and Teh, H. S. (1995). Distinct differentiative stages of CD4+CD8+ thymocyte development defined by the lack of coreceptor binding in positive selection. J. Immunol. 154, 2588-2599.
42. Egerton, M., Scollay, R., and Shortman, K. (1990). Kinetics of mature T-cell development in the thymus. Proc. Natl. Acad. Sci. USA 87, 2579-2582.
43. Fehling, H. J., Krotkova, A., Saint-Ruf, C., and von Boehmer, H. (1995). Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Nature 375, 795-798.
44. Frank, S. J., Samelson, L. E., and Klausner, R. D. (1990). The structure and signaling functions of the invariant T cell receptor components. Semin. Immunol. 2, 89-97.
45. Fung-Leung, W. P., Schilham, M. W., Rahemtulla, A., Kundig, T. M., Vollenweider, M., Potter, J., van Ewijk, W., and Mak, T. W. (1991). CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65, 443-449.
46. Gabert, J., Langlet, C., Zamoyska, R., Parnes, J. R., Schmitt-Verhulst, A. M., and Malissen, B. (1987). Reconstitution of MHC class I specificity by transfer of the T cell receptor and Lyt-2 genes. Cell 50, 545-554.
47. Glaichenhaus, N., Shastri, N., Littman, D. R., and Turner, J. M. (1991). Requirement for association of p56lck with CD4 in antigen-specific signal transduction in T cells. Cell 64, 511-520.
48. Godfrey, D. I., and Zlotnik, A. (1993). Control points in early T-cell development. Immunol. Today 14, 547-553.
49. Godfrey, D. I., Kennedy, J., Suda, T., and Zlotnik, A. (1993). A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8-triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150, 4244-4252.
50. Goldrath, A. W., Hogquist, K. A., and Bevan, M. J. (1997). CD8 lineage commitment in the absence of CD8. Immunity 6, 633-642.
51. Gorman, S. D., Sun, Y. H., Zamoyska, R., and Parnes, J. R. (1988). Molecular linkage of the Ly-3 and Ly-2 genes. Requirement of Ly-2 for Ly-3 surface expression. J. Immunol. 140, 3646-3653.
52. Grusby, M. J., Johnson, R. S., Papaioannou, V. E., and Glimcher, L. H. (1991). Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science 253, 1417-1420.
53. Guidos, C. J., Danska, J. S., Fathman, C. G., and Weissman, I. L. (1990). T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J. Exp. Med. 172, 835-845.
54. Guo, J., Hawwari, A., Li, H., Sun, Z., Mahanta, S. K., Littman, D. R., Krangel, M. S., and He, Y. W. (2002). Regulation of the TCRalpha repertoire by the survival window of CD4(+)CD8(+) thymocytes. Nat. Immunol. 3, 469-476.
55. Haks, M. C., Belkowski, S. M., Ciofani, M., Rhodes, M., Lefebvre, J. M., Trop, S., Hugo, P., Zuniga-Pflucker, J. C., and Wiest, D. L. (2003). Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells. J. Immunol. 170, 2853-2861.
56. Hashimoto, K., Sohn, S. J., Levin, S. D., Tada, T., Perlmutter, R. M., and Nakayama, T. (1996). Requirement for p56lck tyrosine kinase activation in T cell receptor-mediated thymic selection. J. Exp. Med. 184, 931-943.
57. Hernandez-Hoyos, G., Sohn, S. J., Rothenberg, E. V., and Alberola-Ila, J. (2000). Lck activity controls CD4/CD8 T cell lineage commitment. Immunity 12, 313-322.
58. Hogquist, K. A., Jameson, S. C., Heath, W. R., Howard, J. L., Bevan, M. J., and Carbone, F. B. (1994). T cell receptor antagonist peptides induce positive selection. Cell 76, 17-27.
59. Huesmann, M., Scott, B., Kisielow, P., and von Boehmer, H. (1991). Kinetics and efficacy of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell 66, 533-540.
60. Irie, H. Y., Mong, M. S., Itano, A., Crooks, M. E., Littman, D. R., Burakoff, S. J., and Robey, E. (1998). The cytoplasmic domain of CD8 beta regulates Lck kinase activation and CD8 T cell development. J. Immunol. 161, 183-191.
61. Irie, H. Y., Ravichandran, K. S., and Burakoff, S. J. (1995). CD8 beta chain influences CD8 alpha chain-associated Lck kinase activity. J. Exp. Med. 181, 1267-1273.
62. Irving, B. A., Alt, F. W., and Killeen, N. (1998). Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280, 905-908.
63. Itano, A., and Robey, E. (2000). Highly efficient selection of CD4 and CD8 lineage thymocytes supports an instructive model of lineage commitment. Immunity 12, 383-389.
64. Itano, A., Kioussis, D., and Robey, E. (1994). Stochastic component to development of class I major histocompatibility complex-specific T cells. Proc. Natl. Acad. Sci. USA 91, 220-224.
65. Itano, A., Salmon, P., Kioussis, D., Tolaini, M., Corbella, P., and Robey, E. (1996). The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells. J Exp. Med. 183, 731-741.
66. Iwashima, M., Irving, B. A., van Oers, N. S., Chan, A. C., and Weiss, A. (1994). Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263, 1136-1139.
67. Iwata, M., Kuwata, T., Mukai, M., Tozawa, Y., and Yokoyama, M. (1996). Differential induction of helper and killer T cells from isolated CD4+CD8+ thymocytes in suspension culture. Eur. J. Immunol. 26, 2081-2086.
68. Izon, D. J., Aster, J. C., He, Y., Weng, A., Karnell, F. G., Patriub, V., Xu, L., Bakkour, S., Rodriguez, C., Allman, D., and Pear, W. S. (2002a). Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16, 231-243.
69. Izon, D. J., Punt, J. A., and Pear, W. S. (2002b). Deciphering the role of Notch signaling in lymphopoiesis. Curr. Opin. Immunol. 14, 192-199.
70. Izon, D. J., Punt, J. A., Xu, L., Karnell, F. G., Allman, D., Myung, P. S., Boerth, N. J., Pui, J. C., Koretzky, G. A., and Pear, W. S. (2001). Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity 14, 253-264.
71. Janeway, C. A., Jr. (1988). T-cell development. Accessories or coreceptors? Nature 335, 208-210.
72. Jenkinson, E. J., Van Ewijk, W., and Owen, J. J. (1981). Major histocompatibility complex antigen expression on the epithelium of the developing thymus in normal and nude mice. J. Exp. Med. 153, 280-292.
73. Kappler, J. W., Roehm, N., and Marrack, P. (1987). T cell tolerance by clonal elimination in the thymus. Cell 49, 273-280.
74. Kawamoto, H., Ohmura, K., Fujimoto, S., Lu, M., Ikawa, T., and Katsura, Y. (2003). Extensive proliferation of T cell lineage-restricted progenitors in the thymus: An essential process for clonal expression of diverse T cell receptor beta chains. Eur. J. Immunol. 33, 606-615.
75. Kaye, J., Hsu, M. L., Sauron, M. E., Jameson, S. C., Gascoigne, N. B., and Hedrick, S. M. (1989). Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature 341, 746-749.
76. Kearse, K. P., Roberts, J. L., Munitz, T. I., Wiest, D. L., Nakayama, T., and Singer, A. (1994a). Developmental regulation of alpha beta T cell antigen receptor expression results from differential stability of nascent TCR alpha proteins within the endoplasmic reticulum of immature and mature T cells. EMBO J. 13, 4504-4514.
77. Kearse, K. P., Williams, D. B., and Singer, A. (1994b). Persistence of glucose residues on core oligosaccharides prevents association of TCR alpha and TCR beta proteins with calnexin and results specifically in accelerated degradation of nascent TCR alpha proteins within the endoplasmic reticulum. EMBO J. 13, 3678-3686.
78. Kearse, K. P., Roberts, J. P., Wiest, D. L., and Singer, A. (1995). Developmental regulation of alpha beta T cell antigen receptor assembly in immature CD4+CD8+ thymocytes. Bioessays 17, 1049-1054.
79. Kisielow, P., Teh, H. S., Bluthmann, H., and von, B. H. (1988). Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 335, 730-733.
80. Koch, U., Lacombe, T. A., Holland, D., Bowman, J. L., Cohen, B. L., Egan, S. E., and Guidos, C. J. (2001). Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1. Immunity 15, 225-236.
81. Koller, B. H., Marrack, P., Kappler, J. W., and Smithies, O. (1990). Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. Science 248, 1227-1230.
82. Kruisbeek, A. M., Fultz, M. J., Sharrow, S. O., Singer, A., and Mond, J. J. (1983). Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells. J. Exp. Med. 157, 1932-1946.
83. Kruisbeek, A. M., Mond, J. J., Fowlkes, B. J., Carmen, J. A., Bridges, S., and Longo, D. L. (1985). Absence of the Lyt-2-, L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting cell function. J. Exp. Med. 161, 1029-1047.
84. Lai, E. C. (2002). Notch cleavage: Nicastrin helps Presenilin make the final cut. Curr. Biol. 12, R200-202.
85. Ledbetter, J. A., and Seaman, W. E. (1982). The Lyt-2, Lyt-3 macromolecules: Structural and functional studies. Immunol. Rev. 68, 197-218.
86. Ledbetter, J. A., Seaman, W. E., Tsu, T. T., and Herzenberg, L. A. (1981). Lyt-2 and lyt-3 antigens are on two different polypeptide subunits linked by disulfide bonds. Relationship of subunits to T cell cytolytic activity. J. Exp. Med. 153, 1503-1516.
87. Leung, R. K., Thomson, K., Gallimore, A., Jones, E., Van, d. B. M., Sierro, S., Alsheikhly, A. R., McMichael, A., and Rahemtulla, A. (2001). Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nat. Immunol. 2, 1167-1173.
88. Levin, S. D., Anderson, S. J., Forbush, K. A., and Perlmutter, R. M. (1993). A dominant-negative transgene defines a role for p56lck in thymopoiesis. EMBO J. 12, 1671-1680.
89. Liao, X. C., and Littman, D. R. (1995). Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 3, 757-769.
90. Linette, G. P., Grusby, M. J., Hedrick, S. M., Hansen, T. H., Glimcher, L. H., and Korsmeyer, S. J. (1994). Bcl-2 is upregulated at the CD4+ CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1, 197-205.
91. Locksley, R. M., Reiner, S. L., Hatam, F., Littman, D. R., and Killeen, N. (1993). Helper T cells without CD4: Control of leishmaniasis in CD4-deficient mice. Science 261, 1448-1451.
92. Love, P. E., Lee, J., and Shores, E. W. (2000). Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection. J. Immunol. 165, 3080-3087.
93. Lucas, J. A., Atherly, L. O., and Berg, L. J. (2002). The absence of Itk inhibits positive selection without changing lineage commitment. J. Immunol. 168, 6142-6151.
94. Lucas, B., Stefanova, I., Yasutomo, K., Dautigny, N., and Germain, R. N. (1999). Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire. Immunity 10, 367-376.
95. Lucas, B., Vasseur, F., and Penit, C. (1995). Stochastic coreceptor shut-off is restricted to the CD4 lineage maturation pathway. J. Exp. Med. 181, 1623-1633.
96. Lundberg, K., Heath, W., Kontgen, F., Carbone, R. F., and Shortman, K. (1995). Intermediate steps in positive selection: Differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes. J. Exp. Med. 181, 1643-1651.
97. Madrenas, J., Wange, R. L., Wang, J. L., Isakov, N., Samelson, L. E., and Germain, R. N. (1995). Zeta phosphorylation without ZAP-70 activation induced by TCR antagonists or partial agonists. Science 267, 515-518.
98. Marth, J. D., Lewis, D. B., Cooke, M. P., Mellins, E. D., Gearn, M. E., Samelson, L. E., Wilson, C. B., Miller, A. D., and Perlmutter, R. M. (1989). Lymphocyte activation provokes modification of a lymphocyte-specific protein tyrosine kinase (p56lck). J. Immunol. 142, 2430-2437.
99. Marth, J. D., Peet, R., Krebs, E. G., and Perlmutter, R. M. (1985). A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA. Cell 43, 393-404.
100. Marusic-Galesic, S., Stephany, D. A., Longo, D. L., and Kruisbeek, A. M. (1988). Development of CD4-CD8+ cytotoxic T cells requires interactions with class I MHC determinants. Nature 333, 180-183.
101. Matechak, E. O., Killeen, N., Hedrick, S. M., and Fowlkes, B. J. (1996). MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 4, 337-347.
102. McCarthy, S. A., Kruisbeek, A. M., Uppenkamp, I. K., Sharrow, S. O., and Singer, A. (1988). Engagement of the CD4 molecule influences cell surface expression of the T-cell receptor on thymocytes. Nature 336, 76-79.
103. Merkenschlager, M., Graf, D., Lovatt, M., Bommhardt, U., Zamoyska, R., and Fisher, A. G. (1997). How many thymocytes audition for selection? J. Exp. Med. 186, 1149-1158.
104. Mombaerts, P., Clarke, A. R., Rudnicki, M. A., Iacomini, J., Itohara, S., Lafaille, J. J., Wang, L., Ichikawa, Y., Jaenisch, R., Hooper, M. L., et al. (1992). Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature 360, 225-231.
105. Muller, K. P., and Kyewski, B. A. (1995). Intrathymic T cell receptor (TcR) targeting in mice lacking CD4 or major histocompatibility complex (MHC) class II: Rescue of CD4 T cell lineage without co-engagement of TcR/CD4 by MHC class II. Eur. J. Immunol. 25, 896-902.
106. Nakayama, T., June, C. H., Munitz, T. I., Sheard, M., McCarthy, S. A., Sharrow, S. O., Samelson, L. E., and Singer, A. (1990). Inhibition of T cell receptor expression and function in immature CD4+CDS+ cells by CD4. Science 249, 1558-1561.
107. Nakayama, T., Singer, A., Hsi, E. D., and Samelson, L. E. (1989). Intrathymic signaling in immature CD4+CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor zeta chain. Nature 341, 651-654.
108. Nakayama, T., Wiest, D. L., Abraham, K. M., Munitz, T. I., Perlmutter, R. M., and Singer, A. (1993). Decreased signaling competence as a result of receptor overexpression: Overexpression of CD4 reduces its ability to activate p56lck tyrosine kinase and to regulate T-cell antigen receptor expression in immature CD4+CD8+ thymocytes. Proc. Natl. Acad. Sci. USA 90, 10534-10538.
109. Noguchi, M., Sarin, A., Aman, M. J., Nakajima, H., Shores, E. W., Henkart, P. A., and Leonard, W. J. (1997). Functional cleavage of the common cytokine receptor gamma chain (gammac) by calpain. Proc. Natl. Acad. Sci. USA 94, 11534-11539.
110. Norment, A. M., and Littman, D. R. (1988). A second subunit of CD8 is expressed in human T cells. EMBO J. 7, 3433-3439.
111. Norment, A. M., Salter, R. D., Parham, P., Engelhard, V. H., and Littman, D. R. (1988). Cell-cell adhesion mediated by CD8 and MHC class I molecules. Nature 336, 79-81.
112. Ohoka, Y., Kuwata, T., Tozawa, Y., Zhao, Y., Mukai, M., Motegi, Y., Suzuki, R., Yokoyama, M., and Iwata, M. (1996). In vitro differentiation and commitment of CD4+CD8+ thymocytes to the CD4 lineage, without TCR engagement. Int. Immunol. 8, 297-306.
113. O'Shea, C. C., Thornell, A. P., Rosewell, I. R., Hayes, B., and Owen, M. J. (1997). Exit of the pre-TCR from the ER/cis-Golgi is necessary for signaling differentiation, proliferation, and allelic exclusion in immature thymocytes. Immunity 7, 591-599.
114. Pearse, M., Wu, L., Egerton, M., Wilson, A., Shortman, K., and Scollay, R. (1989). A murine early thymocyte developmental sequence is marked by transient expression of the interleukin 2 receptor. Proc. Natl. Acad. Sci. USA 86, 1614-1618.
115. Pelchen-Matthews, A., Armes, J. E., Griffiths, G., and Marsh, M. (1991). Differential endocytosis of CD4 in lymphocytic and nonlymphocytic cells. J. Exp. Med. 173, 575-587.
116. Pelchen-Matthews, A., Boulet, I., Littman, D. R., Fagard, R., and Marsh, M. (1992). The protein tyrosine kinase p56lck inhibits CD4 endocytosis by preventing entry of CD4 into coated pits. J. Cell Biol. 117, 279-290.
117. Pena-Rossi, C., Zuckerman, L. A., Strong, J., Kwan, J., Ferris, W., Chan, S., Tarakhovsky, A., Beyers, A. D., and Killeen, N. (1999). Negative regulation of CD4 lineage development and responses by CD5. J. Immunol. 163, 6494-6501.
118. Petrie, H. T., Livak, F., Schatz, D. G., Strasser, A., Crispe, I. N., and Shortman, K. (1993). Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes. J. Exp. Med. 178, 615-622.
119. Philpott, K. L., Viney, J. L., Kay, G., Rastan, S., Gardiner, E. M., Chae, S., Hayday, A. C., and Owen, M. J. (1992). Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells. Science 256, 1448-1452.
120. Pui, J. C., Allman, D., Xu, L., DeRocco, S., Karnell, F. G., Bakkour, S., Lee, J. Y., Kadesch, T., Hardy, R. R., Aster, J. C., and Pear, W. S. (1999). Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299-308.
121. Punt, J. A., Suzuki, H., Granger, L. G., Sharrow, S. O., and Singer, A. (1996). Lineage commitment in the thymus: Only the most differentiated (TCRhibcl-2hi) subset of CD4+CD8+ thymocytes has selectively terminated CD4 or CD8 synthesis. J. Exp. Med. 184, 2091-2099.
122. Radtke, E., Wilson, A., Stark, G., Bauer, M., van Meerwijk, J., MacDonald, H. R., and Aguet, M. (1999). Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547-558.
123. Rahemtulla, A., Fung-Leung, W. P., Schilham, M. W., Kundig, T. M., Sambhara, S. R., Narendran, A., Arabian, A., Wakeham, A., Paige, C. J., Zinkernagel, R. M., et al. (1991). Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353, 180-184.
124. Riberdy, J. M., Mostaghel, E., and Doyle, C. (1998). Disruption of the CD4-major histocompatibility complex class 11 interaction blocks the development of CD4(+) T cells in vivo. Proc. Natl. Acad. Sci. USA 95, 4493-4498.
125. Robey, E. A., Fowlkes, B. J., Gordon, J. W., Kioussis, D., von Boehmer, H., Rarnsdell, F., and Axel, R. (1991). Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell 64, 99-107.
126. Robey, E., Itano, A., Fanslow, W. C., and Fowlkes, B. J. (1994). Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J. Exp. Med. 179, 1997-2004.
127. Robey, E. A., Ramsdell, E., Kioussis, D., Sha, W., Loh, D., Axel, R., and Fowlkes, B. J. (1992). The level of CD8 expression can determine the outcome of thymic selection. Cell 69, 1089-1096.
128. Saint-Ruf, C., Ungewiss, K., Groettrup, M., Bruno, L., Fehling, H. J., and von Boehmer, H. (1994). Analysis and expression of a cloned pre-T cell receptor gene. Science 266, 1208-1212.
129. Samelson, L. E., Phillips, A. E., Luong, E. T., and Klausner, R. D. (1990). Association of the fyn protein-tyrosine kinase with the T-cell antigen receptor. Proc. Natl. Acad. Sci. USA 87, 4358-4362.
130. Schaeffer, E. M., Broussard, C., Debnath, J., Anderson, S., McVicar, D. W., and Schwartzberg, P. L. (2000). Tec family kinases modulate thresholds for thymocyte development and selection. J. Exp. Med. 192, 987-1000.
131. Schmedt, C., and Tarakhovsky, A. (2001). Autonomous maturation of alpha/beta T lineage cells in the absence of COOH-terminal Src kinase (Csk). J. Exp. Med. 193, 815-826.
132. Schmedt, C., Saijo, K., Niidome, T., Kuhn, R., Aizawa, S., and Tarakhovsky, A. (1998). Csk controls antigen receptor-mediated development and selection of T-lineage, cells. Nature 394, 901-904.
133. Schmitt, T. M., and Zuniga-Pflucker, J. C. (2002). Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749-756.
134. Sebzda, E., Choi, M., Fung-Leung, W. P., Mak, T. W., and Ohashi, P. S. (1997). Peptide-induced positive selection of TCR transgenic thymocytes in a coreceptor-independent manner. Immunity 6, 643-653.
135. Seong, R. H., Chamberlain, J. W., and Parnes, J. R. (1992). Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature 356, 718-720.
136. Sha, W. C., Nelson, C. A., Newberry, R. D., Kranz, D. M., Russell, J. H., and Loh, D. Y. (1988). Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 336, 73-76.
137. Sharp, L. L., and Hedrick, S. M. (1999). Commitment to the CD4 lineage mediated by extracellular signal-related kinase mitogen-activated protein kinase and lck signaling. J. Immunol. 163, 6598-6605.
138. Sharp, L. L., Schwarz, D. A., Bott, C. M., Marshall, C. J., and Hedrick, S. M. (1997). The influence of the MAPK pathway on T cell lineage commitment. Immunity 7, 609-618.
139. Shaw, A. S., Amrein, K. E., Hammond, C., Stern, D. F., Sefton, B. M., and Rose, J. K. (1989). The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain. Cell 59, 627-636.
140. Shaw, A. S., Chalupny, J., Whitney, J. A., Hammond, C., Amrein, K. E., Kavathas, P., Sefton, B. M., and Rose, J. K. (1990). Short related sequences in the cytoplasmic domains of CD4 and CD8 mediate binding to the amino-terminal domain of the p56lck tyrosine protein kinase. Mol. Cell. Biol. 10, 1853-1862.
141. Shores, E. W., Huang, K., Tran, T., Lee, E., Grinberg, A., and Love, P. E. (1994). Role of TCR zeta chain in T cell development and selection. Science 266, 1047-1050.
142. Shores, E. W., Tran, T., Grinberg, A., Sommers, C. L., Shen, H., and Love, P. E. (1997). Role of the multiple T cell receptor (TCR)-zeta chain signaling motifs in selection of the T cell repertoire. J. Exp. Med. 185, 893-900.
143. Singer, A., Mizuochi, T., Munitz, T. I., and Gress, R. E. (1986). Role of self antigens in the selection of the developing T cell repertoire. In "Progress in Immunology VI" (B. Cinader and R. G. Miller, Eds.), pp. 60-66. Academic Press, New York.
144. Singer, A., Munitz, T. I., and Gress, R. E. (1987). Specificity of thymic selection and the role of self antigens. Transplant Proc. 19, 107-110.
145. Singer, A. (2002). New perspectives on a developmental dilemma: The kinetic signaling model and the importance of signal duration for the CD4/CD8 lineage decision. Curr. Opin. Immunol. 14, 207-215.
146. Sloan-Lancaster, J., Shaw, A. S., Rothbard, J. B., and Allen, P. M. (1994). Partial T cell signaling: Altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell 79, 913-922.
147. Sohn, S. J., Forbush, K. A., Pan, X. C., and Perlmutter, R. M. (2001). Activated p56lck directs maturation of both CD4 and CD8 single-positive thymocytes. J. Immunol. 166, 2209-2217.
148. Sosinowski, T., Killeen, N., and Weiss, A. (2001). The Src-like adaptor protein downregulates the T cell receptor on CD4+CD8+ thymocytes and regulates positive selection. Immunity 15, 457-466.
149. Stefanova, I., Hemmer, B., Vergelli, M., Martin, R., Biddison, W. E., and Germain, R. N. (2003). TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4, 248-254.
150. Sudo, T., Nishikawa, S., Ohno, N., Akiyama, N., Tamakoshi, M., and Yoshida, H. (1993). Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc. Natl. Acad. Sci. USA 90, 9125-9129.
151. Suzuki, H., Guinter, T. I., Koyasu, S., and Singer, A. (1998). Positive selection of CD4+ T cells by TCR-specific antibodies requires low valency TCR cross-linking: Implications for repertoire selection in the thymus. Eur. J. Immunol. 28, 3252-3258.
152. Suzuki, H., Punt, J. A., Granger, L. G., and Singer, A. (1995). Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: A new perspective on thymic commitment and selection. Immunity 2, 413-425.
153. Swat, W., Dessing, M., von Boehmer, H., and Kisielow, P. (1993). CD69 expression during selection and maturation of CD4+8+ thymocytes. Eur. J. Immunol. 23, 739-746.
154. Takahama, Y., and Singer, A. (1992). Post-transcriptional regulation of early T cell development by T cell receptor signals. Science 258, 1456-1462.
155. Takahama, Y., Shores, E. W., and Singer, A. (1992). Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells. Science 258, 653-656.
156. Takahama, Y., Suzuki, H., Katz, K. S., Grusby, M. J., and Singer, A. (1994). Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC. Nature 371, 67-70.
157. Teh, H. S., Garvin, A. M., Forbush, K. A., Carlow, D. A., Davis, C. B., Littman, D. R., and Perlmutter, R. M. (1991). Participation of CD4 coreceptor molecules in T-cell repertoire selection. Nature 349, 241-243.
158. Teh, H. S., Kishi, H., Scott, B., and von Boehmer, H. (1989). Deletion of autospecific T cells in T cell receptor (TCR) transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules. J. Exp. Med. 169, 795-806.
159. Teh, H. S., Kisielow, P., Scott, B., Kishi, H., Uematsu, Y., Bluthmann, H., and von Boehmer, H. (1988). Thymic major histocompatibility complex antigens and the alpha beta T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229-233.
160. Turka, L. A., Schatz, D. G., Oettinger, M. A., Chun, J. J., Gorka, C., Lee, K., McCormack, W. T., and Thompson, C. B. (1991). Thymocyte expression of RAG-1 and RAG-2: Termination by T cell receptor cross-linking. Science 253, 778-781.
161. Turner, J. M., Brodsky, M. H., Irving, B. A., Levin, S. D., Perlmutter, R. M., and Littman, D. R. (1990). Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60, 755-765.
162. Van Ewijk, W., Rouse, R. V., and Weissman, I. L. (1980). Distribution of H-2 microenvironments in the mouse thymus. Immunoelectron microscopic identification of I-A and H-2K bearing cells. J. Histochem. Cytochem. 28, 1089-1099.
163. van Meerwijk, J. P., and Germain, R. N. (1993). Development of mature CD8+ thymocytes: Selection rather than instruction? Science 261, 911-915.
164. van Oers, N. S., Garvin, A. M., Davis, C. B., Forbush, K. A., Carlow, D. A., Littman, D. R., Perlmutter, R. M., and Teh, H. S. (1992). Disruption of CD8-dependent negative and positive selection of thymocytes is correlated with a decreased association between CD8 and the protein tyrosine kinase, p56lck. Eur. J. Immunol. 22, 735-743.
165. van Oers, N. S., Killeen, N., and Weiss, A. (1994). ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells. Immunity 1,675-685.
166. Veillette, A., Bookman, M. A., Horak, E. M., and Bolen, J. B. (1988). The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55, 301-308.
167. Veillette, A., Bookman, M. A., Horak, E. M., Samelson, L. E., and Bolen, J. B. (1989). Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature 338, 257-259.
168. Voll, R. E., Jimi, E., Phillips, R. J., Barber, D. F., Rincon, M., Hayday, A. C., Flavell, R. A., and Ghosh, S. (2000). NF-kappa B activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677-689.
169. Wang, F., Huang, C. Y., and Kanagawa, O. (1998). Rapid deletion of rearranged T cell antigen receptor (TCR) Valpha-Jalpha segment by secondary rearrangement in the thymus: Role of continuous rearrangement of TCR alpha chain gene and positive selection in the T cell repertoire formation. Proc. Natl. Acad. Sci. USA 95, 11834-11839.
170. Wiest, D. L., Ashe, J. M., Abe, R., Bolen, J. B., and Singer, A. (1996). TCR activation of ZAP70 is impaired in CD4+CD8+ thymocytes as a consequence of intrathymic interactions that diminish available p56lck. Immunity 4, 495-504.
171. Wiest, D. L., Yuan, L., Jefferson, J., Benveniste, P., Tsokos, M., Klausner, R. D., Glimcher, L. H., Samelson, L. E., and Singer, A. (1993). Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: Basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J. Exp. Med. 178, 1701-1712.
172. Wilkinson, B., and Kaye, J. (2001). Requirement for sustained MAPK signaling in both CD4 and CD8 lineage commitment: A threshold model. Cell Immunol. 211, 86-95.
173. Wilson, A., MacDonald, H. R., and Radtke, F. (2001). Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194, 1003-1012.
174. Wyer, J. R., Willcox, B. E., Gao, G. F., Gerth, U. C., Davis, S. J., Bell, J. I., van der Merwe, P. A., and Jakobsen, B. K. (1999). T cell receptor and coreceptor CD8 alphaalpha bind peptide-MHC independently and with distinct kinetics. Immunity 10, 219-225.
175. Yasutomo, K., Doyle, C., Miele, L., Fuchs, C., and Germain, R. N. (2000a). The duration of antigen receptor signaling determines CD4+ versus CD8+ T-cell lineage fate. Nature 404, 506-510.
176. Yasutomo, K., Lucas, B., and Germain, R. N. (2000b). TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting cell type. J. Immunol. 165, 3015-3022.
177. Yu, Q., Erman, B., Bhandoola, A., Sharrow, S. O., and Singer, A. (2003). In vitro evidence that cytokine receptor signals are required for differentiation of double positive thymocytes into functionally mature CD8+ T cells. J. Exp. Med. 197, 475-487.
178. Zamoyska, R., Vollmer, A. C., Sizer, K. C., Liaw, C. W., and Parnes, J. R. (1985). Two Lyt-2 polypeptides arise from a single gene by alternative splicing patterns of mRNA. Cell 43, 153-163.
179. Zerrahm, J., Held, W., and Raulet, D. H. (1997). The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627-636.
180. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P., and Samelson, L. E. (1998). LAT: The ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92, 83-92.
181. Zijlstra, M., Bix, M., Simister, N. E., Loring, J. M., Raulet, D. H., and Jaenisch, R. (1990). Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344, 742-746.