t-cell development and the CD4-CD8 lineage decision

Nature Reviews Immunology

Volumn 2, Issue 5, 2002, Pages 309-322

  Germain, Ronald N ^a  

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CD8 ANTIGEN; LIGAND; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; T LYMPHOCYTE RECEPTOR; HISTOCOMPATIBILITY ANTIGEN; LYMPHOCYTE ANTIGEN RECEPTOR; MEMBRANE PROTEIN; NOTCH RECEPTOR;

CELL FATE; CELL LINEAGE; CELL MATURATION; LYMPHOCYTE DIFFERENTIATION; MAJOR HISTOCOMPATIBILITY COMPLEX; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE; ANIMAL; BIOLOGICAL MODEL; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; IMMUNOLOGY; METABOLISM; PHYSIOLOGY; SIGNAL TRANSDUCTION; THYMUS;

ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; CELL LINEAGE; HISTOCOMPATIBILITY ANTIGENS; MEMBRANE PROTEINS; MODELS, IMMUNOLOGICAL; RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA; RECEPTORS, NOTCH; SIGNAL TRANSDUCTION; THYMUS GLAND;

EID: 0036582215     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri798     Document Type: Review

References (138)

1. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313-319 (2000).
2. Germain, R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T-lymphocyte activation. Cell 76, 287-299 (1994).
3. Biddison, W. E., Rao, P. E., Talle, M. A., Goldstein, G. & Shaw, S. Possible involvement of the OKT4 molecule in T-cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens. J. Exp. Med. 156, 1065-1076 (1982).
4. Swain, S. L. T-cell subsets and the recognition of MHC class. Immunol. Rev. 74, 129-142 (1983).
5. Janeway, C. A. Jr. The T-cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T-cell activation. Annu. Rev. Immunol. 10, 645-674 (1992).
6. Robey, E. & Fowlkes, B. J. Selective events in T-cell development. Annu. Rev. Immunol. 12, 675-705 (1994).
7. + 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 (1985). One of the very first papers to show that the class of MHC molecule that is recognized controls the development of a particular mature co-receptor-defined T-cell subset.
8. Teh, H. S. et al. Thymic major histocompatibility complex antigens and the αβ T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229-233 (1988). The first use of TCR-transgenic mice to reveal the relationship between MHC class-specificity in foreign antigen recognition and co-receptor-defined lineage development in the thymus.
9. Marusic-Galesic, S., Longo, D. L. & Kruisbeek, A. M. Preferential differentiation of T-cell receptor specificities based on the MHC glycoproteins encountered during development. Evidence for positive selection. J. Exp. Med. 169, 1619-1630 (1989).
10. + single-positive T-cell development.
11. Robey, E. A., Fowlkes, B. J. & Pardoll, D. M. Molecular mechanisms for lineage commitment in T-cell development. Semin. Immunol. 2, 25-34 (1990).
12. Borgulya, P., Kishi, H., Müller, U., Kirberg, J. & von Boehmer, H. Development of the CD4 and CD8 lineage of T cells: instruction versus selection. EMBO J. 10, 913-918 (1991).
13. Robey, E. A. et al. Thymic selection in CD8-transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell 64, 99-107 (1991). References 11-13 set out the original proposals for the 'instruction' versus 'selection' models of lineage commitment and development. They also provided the first experimental tests of the models, which looked for 'rescue' with co-receptor transgenes.
14. Davis, C. B., Killeen, N., Crooks, M. E., Raulet, D. & Littman, D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73, 237-247 (1993).
15. Chan, S. H., Cosgrove, D., Waltzinger, C., Benoist, C. & Mathis, D. Another view of the selective model of thymocyte selection. Cell 73, 225-236 (1993).
16. + thymocytes: selection rather than instruction? Science 261, 911-915 (1993). References 15 and 16 conclude that stochastic choice/selection is more probable than instruction, based on the appearance of transitional-phenotype cells in various MHC-deficient mice.
17. von Boehmer, H. & Kisielow, P. Lymphocyte lineage commitment: instruction versus selection. Cell 73, 207-208 (1993).
18. Chan, S. H., Benoist, C. & Mathis, D. In favor of the selective model of positive selection. Semin. Immunol. 6, 241-248 (1994).
19. van Meerwijk, J. P. M., O'Connell, E. M. & Germain, R. N. Evidence for lineage commitment and initiation of positive selection by thymocytes with intermediate surface phenotypes. J. Immunol. 154, 6314-6323 (1995).
20. Kersh, G. J. & Hedrick, S. M. Role of TCR specificity in CD4 versus CD8 lineage commitment. J. Immunol. 154, 1057-1068 (1995).
21. von Boehmer, H. CD4/CD8 lineage commitment: back to instruction? J. Exp. Med. 183, 713-715 (1996).
22. Itano, A. et al. The cytoplasmic domain of CD4 promotes the development of CD4-lineage T cells. J. Exp. Med. 183, 731-741 (1996).
23. Matechak, E. O., Killeen, N., Hedrick, S. M. & Fowlkes, B. J. MHC class-II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 4, 337-347 (1996). References 22 and 23 contain the initial descriptions of the 'strength of signal' model.
24. Ohoka, Y. et al. Regulation of thymocyte lineage commitment by the level of classical protein kinase C activity. J. Immunol. 158, 5707-5716 (1997).
25. + single-positive T cells.
26. Bommhardt, U., Cole, M. S., Tso, J. Y. & Zamoyska, R. Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus. Eur. J. Immunol. 27, 1152-1163 (1997).
27. Goldrath, A. W., Hogquist, K. A. & Bevan, M. J. CD8-lineage commitment in the absence of CD8. Immunity 6, 633-642 (1997).
28. Sebzda, E., Choi, M., Fung-Leung, W. P., Mak, T. W. & Ohashi, P. S. Peptide-induced positive selection of TCR-transgenic thymocytes in a coreceptor-independent manner. Immunity 6, 643-653 (1997).
29. Basson, M. A., Bommhardt, U., Cole, M. S., Tso, J. Y. & Zamoyska, R. CD3 ligation on immature thymocytes generates antagonist-like signals appropriate for CD8 lineage commitment, independently of T-cell receptor specificity. J. Exp. Med. 187, 1249-1260 (1998).
30. Basson, M. A., Bommhardt, U., Mee, P. J., Tybulewicz, V. L. & Zamoyska, R. Molecular requirements for lineage commitment in the thymus - antibody-mediated receptor engagements reveal a central role for Lck in lineage decisions. Immunol. Rev. 165, 181-194 (1998).
31. + SP thymocytes. Immunity 12, 537-546 (2000).
32. Hernandez-Hoyos, G., Sohn, S. J., Rothenberg, E. V. & Alberola-Ila, J. Lck activity controls CD4/CD8 T-cell lineage commitment. Immunity 12, 313-322 (2000).
33. + T-cell lineage fate. Nature 404, 506-510 (2000). This study used a re-aggregate culture system to separate early and late signals through the TCR and co-receptor in controlling thymocyte development. It showed that signal duration during the initiation of positive selection 'instructs' lineage choice and is controlled by co-operation between the TCR and co-receptors.
34. + T cells. Immunity 13, 59-71 (2000).
35. Itano, A. & Robey, E. Highly efficient selection of CD4- and CD8-lineage thymocytes supports an instructive model of lineage commitment. Immunity 12, 383-389 (2000).
36. Watanabe, N., Arase, H., Onodera, M., Ohashi, P. S. & Saito, T. The quantity of TCR signal determines positive selection and lineage commitment of T cells. J. Immunol. 165, 6252-6261 (2000).
37. Radtke, F. et al. Deficient T-cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547-558 (1999).
38. Pui, J. C. et al. Notch1 expression in early lymphopoiesis influences B- versus T-lineage determination. Immunity 11, 299-308 (1999).
39. Wilson, A., MacDonald, H. R. & Radtke, F. Notch-1-deficient common lymphoid precursors adopt a B-cell fate in the thymus. J. Exp. Med. 194, 1003-1012 (2001).
40. Michie, A. M. et al. Clonal characterization of a bipotent T-cell and NK-cell progenitor in the mouse fetal thymus. J. Immunol. 164, 1730-1733 (2000).
41. - triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150, 4244-4252 (1993).
42. Groettrup, M. et al. A novel disulfide-linked heterodimer on pre-T cells consists of the T-cell receptor β-chain and a 33 kD glycoprotein. Cell 75, 283-294 (1993).
43. von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T-cell receptor. Annu. Rev. Immunol. 15, 433-452 (1997).
44. Aifantis, I., Feinberg, J., Fehling, H. J., Di Santo, J. P. & von Boehmer, H. Early T-cell receptor-β gene expression is regulated by the pre-T-cell-receptor-CD3 complex. J. Exp. Med. 190, 141-144 (1999).
45. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869-877 (1992).
46. Shinkai, Y. et al. Restoration of T-cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259, 822-825 (1993).
47. van Oers, N. S., von Boehmer, H. & Weiss, A. The pre-T-cell receptor (TCR) complex is functionally coupled to the TCR-ζ subunit. J. Exp. Med. 182, 1585-1590 (1995).
48. Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435-438 (1995).
49. van Oers, N. S., Lowin-Kropf, B., Finlay, D., Connolly, K. & Weiss, A. αβ T-cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity 5, 429-436 (1996).
50. Clements, J. L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T-cell development. Science 281, 416-419 (1998).
51. von Boehmer, H., Teh, H. S. & Kisielow, P. The thymus selects the useful, neglects the useless and destroys the harmful. Immunol. Today 10, 57-61 (1989). A seminal description of the TCR-dependent selection events that control thymocyte fate.
52. Merkenschlager, M. et al. How many thymocytes audition for selection? J. Exp. Med. 186, 1149-1158 (1997).
53. Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T-cell repertoire prior to positive and negative selection. Cell 88, 627-636 (1997).
54. Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395-402 (1988).
55. Anderson, S. J., Levin, S. D. & Perlmutter, R. M. Involvement of the protein tyrosine kinase p56lck in T-cell signaling and thymocyte development. Adv. Immunol. 56, 151-178 (1994).
56. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263-274 (1994).
57. Kane, L. R. Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242-249 (2000).
58. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T-cell receptor to cellular activation. Cell 92, 83-92 (1998).
59. Kuo, C. T. & Leiden, J. M. Transcriptional regulation of T-lymphocyte development and function. Annu. Rev. Immunol. 17, 149-187 (1999).
60. Germain, R. N. & Stefanova, I. The dynamics of T-cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467-522 (1999).
61. Germain, R. N. The T-cell receptor for antigen: signaling and ligand discrimination. J. Biol. Chem. 276, 35222-35226 (2001).
62. Madrenas, J., Chau, L. A., Smith, J., Bluestone, J. A. & Germain, R. N. The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands. J. Exp. Med. 185, 219-229 (1997).
63. Hampl, J., Chien, Y. H. & Davis, M. M. CD4 augments the response of a T cell to agonist but not to antagonist ligands. Immunity 7, 379-385 (1997).
64. Bosselut, R. et al. 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 (1999).
65. Sawada, S. & Littman, D. R. Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene. Mol. Cell. Biol. 11, 5506-5515 (1991).
66. Sawada, S., Scarborough, J. D., Killeen, N. & Littman, D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T-lymphocyte development. Cell 77, 917-929 (1994).
67. Ellmeier, W., Sunshine, M. J., Losos, K., Hatam, F. & Littman, D. R. An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7, 537-547 (1997).
68. Ellmeier, W., Sawada, S. & Littman, D. R. The regulation of CD4 and CD8 coreceptor gene expression during T-cell development. Annu. Rev. Immunol. 17, 523-554 (1999).
69. Hostert, A. et al. A CD8 genomic fragment that directs subset-specific expression of CD8 in transgenic mice. J. Immunol. 158, 4270-4281 (1997).
70. Hostert, A. et al. A region in the CD8 gene locus that directs expression to the mature CD8 T-cell subset in transgenic mice. Immunity 7, 525-536 (1997).
71. Adlam, M., Duncan, D. D., Ng, D. K. & Siu, G. Positive selection induces CD4 promoter and enhancer function. Int. Immunol. 9, 877-887 (1997).
72. Hostert, A. et al. Hierarchical interactions of control elements determine CD8α gene expression in subsets of thymocytes and peripheral T cells. Immunity 9, 497-508 (1998).
73. Kim, H. K. & Siu, G. The notch pathway intermediate HES-1 silences CD4 gene expression. Mol. Cell. Biol. 18, 7166-7175 (1998).
74. Zou, Y. R. et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nature Genet. 29, 332-336 (2001).
75. Leung, R. K. et al. Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nature Immunol. 2, 1167-1173 (2001). This report argues for a stochastic/selection model, on the basis of MHC class-II-dependent production of CD8-lineage cells after the elimination of CD4 silencer function. See the text and legend to FIG. 4 for an alternative interpretation of these data that is consistent with an instruction model.
76. Davis, C. B. & Littman D. R. Thymocyte lineage commitment: is it instructed or stochastic? Curr. Opin. Immunol. 6, 266-272 (1994).
77. Itano, A., Kioussis, D. & Robey, E. Stochastic component to development of class I major-histocompatibility-complex-specific T cells. Proc. Natl Acad. Sci. USA 91, 220-224 (1994).
78. + helper T cells in class II major histocompatibility complex mutant mice. J. Exp. Med. 179, 1997-2004 (1994).
79. Guidos, C. J., Danska, J. S., Fathman, C. G. & Weissman, I. L. 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 (1990). An initial description of intermediate surface-antigen phenotypes that accompany the double-positive to single-positive transition. The concept of 'linear' co-receptor loss that arose from this paper was responsible for the difficulty in correctly interpreting later studies of intermediate-phenotype cells in MHC-deficient mice.
80. Crump, A. L., Grusby, M. J., Glimcher, L. H. & Cantor, H. 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 (1993).
81. + T-cell lineages: a new perspective on thymic commitment and selection. Immunity 2, 413-425 (1995).
82. hi thymocytes. J. Exp. Med. 181, 1643-1651 (1995).
83. + single-positive T cells.
84. low coreceptor-skewed thymocytes into mature CD8 single-positive cells independent of MHC class-I recognition. Eur. J. Immunol. 27, 2024-2032 (1997).
85. Correia-Neves, M., Mathis, D. & Benoist, C. A molecular chart of thymocyte positive selection. Eur. J. Immunol. 31, 2583-2592 (2001).
86. Seong, R. H., Chamberlain, J. W. & Parnes, J. R. Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature 356, 718-720 (1992).
87. Itano, A., Cado, D., Chan, F. K. & Robey, E. A role for the cytoplasmic tail of the β-chain of CD8 in thymic selection. Immunity 1, 287-290 (1994).
88. Veillette, A., Zuniga-Pflucker, J. C., Bolen, J. B. & Kruisbeek, A. M. Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways. J. Exp. Med. 170, 1671-1680 (1989). The first report of marked asymmetry of Lck association with CD4 versus CD8 in thymocytes.
89. + 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 (1993).
90. low thymocytes selected by a transgenic T-cell receptor on major histocompatibility complex class I molecules. Eur. J. Immunol. 24, 1982-1987 (1994).
91. Kisielow, P. & Miazek, A. Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T-cell receptor. J. Exp. Med. 181, 1975-1984 (1995).
92. Wilkinson, R. W., Anderson, G., Owen, J. J. & Jenkinson, E. J. Positive selection of thymocytes involves sustained interactions with the thymic microenvironment. J. Immunol. 155, 5234-5240 (1995).
93. Kirberg, J., Berns, A. & von Boehmer, H. Peripheral T-cell survival requires continual ligation of the T-cell receptor to major-histocompatibility-complex-encoded molecules. J. Exp. Med. 186, 1269-1275 (1997).
94. Yasutomo, K., Lucas, B. & Germain, R. N. 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 (2000).
95. + T cells in vivo. Proc. Natl Acad. Sci. USA 95, 4493-4498 (1998).
96. + thymocytes. Nature 333, 742-746 (1988).
97. Wilkinson, B. & Kaye, J. Requirement for sustained MAPK signaling in both CD4 and CD8 lineage commitment: a threshold model. Cell. Immunol. 211, 86-95 (2001).
98. Shao, H., Wilkinson, B., Lee, B. Han, P. C. & Kaye, J. Slow accumulation of active mitogen-activated protein kinase during thymocyte differentiation regulates the temporal pattern of transcription-factor gene expression. J. Immunol. 163, 603-610 (1999).
99. Chan, S., Correia-Neves, M., Dierich, A., Benoist, C. & Mathis, D. Visualization of CD4/CD8 T-cell commitment. J. Exp. Med. 188, 2321-2333 (1998).
100. Chan, S., Correia-Neves, M., Benoist, C. & Mathis, D. CD4/CD8 lineage commitment: matching fate with competence. Immunol. Rev. 165, 195-207 (1998).
101. Bommhardt, U., Basson, M. A., Krummrei, U. & Zamoyska, R. 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 (1999).
102. Shao, H., Rubin, E. M., Chen, L. Y. & Kaye, J. A role for Ras signaling in coreceptor regulation during differentiation of a double-positive thymocyte cell line. J. Immunol. 159, 5773-5776 (1997).
103. Lorenz, U., Ravichandran, K. S., Burakoff, S. J. & Neel, B. G. Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness. Proc. Natl Acad. Sci. USA 93, 9624-9629 (1996).
104. Pani, G., Fischer, K. D., Mlinaric-Rascan, I. & Siminovitch, K. A. Signaling capacity of the T-cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase. J. Exp. Med. 184, 839-852 (1996).
105. Plas, D. R. et al. Direct regulation of ZAP-70 by SHP-1 in T-cell antigen-receptor signaling. Science 272, 1173-1176 (1996).
106. Carter, J. D., Neel, B. G. & Lorenz, U. The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int. Immunol. 11, 1999-2014 (1999).
107. Zhang, J. et al. Involvement of the SHP-1 tyrosine phosphatase in regulation of T-cell selection. J. Immunol. 163, 3012-3021 (1999).
108. Johnson, K. G., LeRoy, F. G., Borysiewicz, L. K. & Matthews, R. J. TCR signaling thresholds regulating T-cell development and activation are dependent upon SHP-1. J. Immunol. 162, 3802-3813 (1999).
109. Plas, D. R. et al. Cutting edge: the tyrosine phosphatase SHP-1 regulates thymocyte positive selection. J. Immunol. 162, 5680-5684 (1999).
110. Chiang, G. G. & Sefton, B. M. Specific dephosphorylation of the Lck tyrosine-protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 276, 23173-23178 (2001).
111. Felli, M. P. et al. Expression pattern of notch1, -2 and -3 and Jagged1 and -2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T-cell development. Int. Immunol. 11, 1017-1025 (1999).
112. Robey, E. Notch in vertebrates. Curr. Opin. Genet. Dev. 7, 551-557 (1997).
113. Osborne, B. & Miele, L. Notch and the immune system. Immunity 11, 653-663 (1999).
114. Anderson, G., Pongracz, J., Parnell, S. & Jenkinson, E. J. Notch-ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T-cell receptor signaling. Eur. J. Immunol. 31, 3349-3354 (2001).
115. Robey, E. et al. An activated form of Notch influences the choice between CD4 and CD8 T-cell lineages. Cell 87, 483-492 (1996). This study concludes, from the phenotype of mice that express an active Notch1 transgene, that Notch signaling has a central role in CD4-CD8 lineage choice.
116. Jimenez, E. et al. Distinct mechanisms contribute to generate and change the CD4:CD8 cell ratio during thymus development: a role for the Notch ligand, Jagged1. J. Immunol. 166, 5898-5908 (2001).
117. + SP thymocytes. Immunity 13, 73-84 (2000). This study presents evidence from a different active Notch1-transgenic model that Notch contributes to the survival of both developing CD4- and CD8-lineage cells; it argues against the concept that Notch has a selective role in the CD8 pathway.
118. + single-positive T-cell development.
119. + thymocytes by modulating TCR signal strength. Immunity 14, 253-264 (2001).
120. Davey, G. M. et al. Preselection thymocytes are more sensitive to T-cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867-1874 (1998).
121. Lucas, B., Stefanova, I., Yasutomo, K., Dautigny, N. & Germain, R. N. 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 (1999).
122. Rothenberg, E. V. Stepwise specification of lymphocyte developmental lineages. Curr. Opin. Genet. Dev. 10, 370-379 (2000).
123. Matzinger, P. & Guerder, S. Does T-cell tolerance require a dedicated antigen-presenting cell? Nature 338, 74-76 (1989).
124. Sant'Angelo, D. B. et al. A molecular map of T-cell development. Immunity 9, 179-186 (1998).
125. Alberola-Ila, J., Forbush, K. A., Seger, R., Krebs, E. G. & Perlmutter, R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373, 620-623 (1995).
126. Alberola-Ila, J., Hogquist, K. A., Swan, K. A., Bevan, M. J. & Perlmutter, R. M. Positive and negative selection invoke distinct signaling pathways. J. Exp. Med. 184, 9-18 (1996).
127. O'Shea, C. C., Crompton, T., Rosewell, I. R., Hayday, A. C. & Owen, M. J. Raf regulates positive selection. Eur. J. Immunol. 26, 2350-2355 (1996).
128. Mariathasan, S., Ho, S. S., Zakarian, A. & Ohashi, P. S. Degree of ERK activation influences both positive and negative thymocyte selection. Eur. J. Immunol. 30, 1060-1068 (2000).
129. Gong, Q. et al. Disruption of T-cell signaling networks and development by Grb2 haploid insufficiency. Nature Immunol. 2, 29-36 (2001).
130. Mariathasan, S. et al. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167, 4966-4973 (2001).
131. Bain, G. et al. Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nature Immunol. 2, 165-171 (2001).
132. Engel, I., Johns, C., Bain, G., Rivera, R. R. & Murre, C. Early thymocyte development is regulated by modulation of E2A protein activity. J. Exp. Med. 194, 733-745 (2001).
133. Pages, G. et al. Defective thymocyte maturation in p44 MAP kinase (Erk-1)-knockout mice. Science 286, 1374-1377 (1999).
134. Anderson, G., Jenkinson, E. J., Moore, N. C. & Owen, J. J. MHC class-II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70-73 (1993).
135. Bendelac, A., Matzinger, P., Seder, R. A., Paul, W. E. & Schwartz, R. H. Activation events during thymic selection. J. Exp. Med. 175, 731-742 (1992).
136. + thymocytes. Eur. J. Immunol. 22, 2367-2372 (1992).
137. Koch, U. et al. Subversion of the T/B lineage decision in the thymus by lunatic-fringe-mediated inhibition of Notch-1. Immunity 15, 225-236 (2001).
138. + stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1, 197-205 (1994).