Zoned out: functional mapping of stromal signaling microenvironments in the thymus

Annual Review of Immunology

Volumn 25, Issue , 2007, Pages 649-679

  Petrie, Howard T ^a   Zúñiga Pflücker, Juan Carlos ^b  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b Sunnybrook Health Sciences Centre   (Canada)

Author keywords

Chemokines; IL 7; Notch ligands; Stromal cells; T cell development; Thymus

Indexed keywords

BRAIN CORTEX; CELL FUNCTION; MEDULLA OBLONGATA; MICROENVIRONMENT; NONHUMAN; PRIORITY JOURNAL; REVIEW; STEM CELL; STROMA CELL; T LYMPHOCYTE; THYMUS;

ANIMALS; BONE MARROW; CELL DIFFERENTIATION; CELL MOVEMENT; HEMATOPOIETIC STEM CELLS; HUMANS; SIGNAL TRANSDUCTION; STROMAL CELLS; T-LYMPHOCYTES; THYMUS GLAND;

EID: 34247882592     PISSN: 07320582     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.immunol.23.021704.115715     Document Type: Review

References (232)

1. Goldschneider I, Komschlies KL, Greiner DL. 1986. Studies of thymocytopoiesis in rats and mice. I. Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors. J. Exp. Med. 163:1-17
2. Wallis VJ, Leuchars E, Chwalinski S, Davies AJ. 1975. On the sparse seeding of bone marrow and thymus in radiation chimaeras. Transplantation 19:2-11
3. Foss DL, Donskoy E, Goldschneider I. 2001. The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J. Exp. Med. 193:365-74
4. Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zúñiga- Pflücker JC, Petrie HT. 2004. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity 20:735-45
5. Weerkamp F, Baert MR, Brugman MH, Dik WA, de Haas EF, et al. 2006. Human thymus contains multipotent progenitors with T/B lymphoid, myeloid, and erythroid lineage potential. Blood 107:3131-37
6. Lu M, Tayu R, Ikawa T, Masuda K, Matsumoto I, et al. 2005. The earliest thymic progenitors in adults are restricted to T, NK, and dendritic cell lineage and have a potential to form more diverse TCRβ chains than fetal progenitors. J. Immunol. 175:5848-56
7. Schwarz BA, Bhandoola A. 2004. Circulating hematopoietic progenitors with T lineage potential. Nat. Immunol. 5:953-60
8. - triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150:4244-52
9. Petrie HT, Pearse M, Scollay R, Shortman K. 1990. Development of immature thymocytes: initiation of CD3, CD4, and CD8 acquisition parallels down-regulation of the interleukin 2 receptor α chain. Eur. J. Immunol. 20:2813-15
10. Fowlkes BJ, Edison L, Mathieson BJ, Chused TM. 1985. Early T lymphocytes. Differentiation in vivo of adult intrathymic precursor cells. J. Exp. Med. 162:802-22
11. Penit C. 1988. Localization and phenotype of cycling and postcycling murine thymocytes studied by simultaneous detection of bromodeoxyuridine and surface antigens. J. Histochem. Cytochem. 36:473-78
12. Brumby M, Metcalf D. 1967. Migration of cells to the thymus demonstrated by parabiosis. Proc. Soc. Exp. Biol. Med. 124:99-103
13. Ezine S, Weissman IL, Rouse RV. 1984. Bone marrow cells give rise to distinct cell clones within the thymus. Nature 309:629-31
14. Kyewski BA. 1987. Seeding of thymic microenvironments defined by distinct thymocytestromal cell interactions is developmentally controlled. J. Exp. Med. 166:520-38
15. Brahim F, Osmond DG. 1970. Migration of bone marrow lymphocytes demonstrated by selective bone marrow labeling with thymidine-H3. Anat. Rec. 168:139-59
16. Ceredig R, Schreyer M. 1984. Immunohistochemical localization of host and donor-derived cells in the regenerating thymus of radiation bone marrow chimeras. Thymus 6:15-26
17. Raviola E, Karnovsky MJ. 1972. Evidence for a blood-thymus barrier using electronopaque tracers. J. Exp. Med. 136:466-98
18. Kato S, Schoefl GI. 1989. Microvasculature of normal and involuted mouse thymus. Light- and electron-microscopic study. Acta Anat. (Basel) 135:1-11
19. Ushiki T. 1986. A scanning electron-microscopic study of the rat thymus with special reference to cell types and migration of lymphocytes into the general circulation. Cell Tiss. Res. 244:285-98
20. Lind EF, Prockop SE, Porritt HE, Petrie HT. 2001. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194:127-34
21. Porritt HE, Gordon K, Petrie HT. 2003. Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J. Exp. Med. 198:957-62
22. Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, et al. 1993. The thymic microenvironment. Immunol. Today 14:445-59
23. Silva-Santos B, Pennington DJ, Hayday AC. 2005. Lymphotoxin-mediated regulation of γδ cell differentiation by αβ T cell progenitors. Science 307:925-28
24. Boehm T, Scheu S, Pfeffer K, Bleul CC. 2003. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J. Exp. Med. 198:757-69
25. Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER. 1998. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl. Acad. Sci. USA 95:11822-27
26. Canelles M, Park ML, Schwartz OM, Fowlkes BJ. 2003. The influence of the thymic environment on the CD4-versus-CD8 T lineage decision. Nat. Immunol. 4:756-64
27. Shortman K, Egerton M, Spangrude GJ, Scollay R. 1990. The generation and fate of thymocytes. Semin. Immunol. 2:3-12
28. Aspinall R, Andrew D. 2000. Thymic involution in aging. J. Clin. Immunol. 20:250-56
29. Haynes BF, Sempowski GD, Wells AF, Hale LP. 2000. The human thymus during aging. Immunol. Res. 22:253-61
30. Madri JA, Graesser D. 2000. Cell migration in the immune system: the evolving interrelated roles of adhesion molecules and proteinases. Dev. Immunol. 7:103-16
31. Springer TA. 1994. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301-14
32. Scimone ML, Aifantis I, Apostolou I, von Boehmer H, von Andrian UH. 2006. A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. Proc. Natl. Acad. Sci. USA 103:7006-11
33. Lepique AP, Palencia S, Irjala H, Petrie HT. 2003. Characterization of vascular adhesion molecules that may facilitate progenitor homing in the postnatal mouse thymus. Clin. Dev. Immunol. 10:27-33
34. Reza JN, Ritter MA. 1994. Differential expression of adhesion molecules within the human thymus. Dev. Immunol. 4:55-64
35. Perry SS, Wang H, Pierce LJ, Yang AM, Tsai S, Spangrude GJ. 2004. L-selectin defines a bone marrow analog to the thymic early T-lineage progenitor. Blood 103:2990-96
36. Xu J, Grewal IS, Geba GP, Flavell RA. 1996. Impaired primary T cell responses in L-selectin-deficient mice. J. Exp. Med. 183:589-98
37. Rossi FM, Corbel SY, Merzaban JS, Carlow DA, Gossens K, et al. 2005. Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat. Immunol. 6:626-34
38. Arroyo AG, Yang JT, Rayburn H, Hynes RO. 1999. α4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity 11:555-66
39. Arroyo AG, Yang JT, Rayburn H, Hynes RO. 1996. Differential requirements for α4 integrins during fetal and adult hematopoiesis. Cell 85:997-1008
40. Prockop SE, Palencia S, Ryan CM, Gordon K, Gray D, Petrie HT. 2002. Stromal cells provide the matrix for migration of early lymphoid progenitors through the thymic cortex. J. Immunol. 169:4354-61
41. Salomon DR, Crisa L, Mojcik CF, Ishii JK, Klier G, Shevach EM. 1997. Vascular cell adhesion molecule-1 is expressed by cortical thymic epithelial cells and mediates thymocyte adhesion. Implications for the function of α4β1 (VLA4) integrin in T-cell development. Blood 89:2461-71
42. Ruiz P, Wiles MV, Imhof BA. 1995. Alpha 6 integrins participate in pro-T cell homing to the thymus. Eur. J. Immunol. 25:2034-41
43. Wu L, Kincade PW, Shortman K. 1993. The CD44 expressed on the earliest intrathymic precursor population functions as a thymus homing molecule but does not bind to hyaluronate. Immunol. Lett. 38:69-75
44. Johnston B, Butcher EC. 2002. Chemokines in rapid leukocyte adhesion triggering and migration. Semin. Immunol. 14:83-92
45. Robertson P, Means TK, Luster AD, Scadden DT. 2006. CXCR4 and CCR5 mediate homing of primitive bone marrow-derived hematopoietic cells to the postnatal thymus. Exp. Hematol. 34:308-19
46. Liu C, Ueno T, Kuse S, Saito F, Nitta T, et al. 2005. The role of CCL21 in recruitment of T-precursor cells to fetal thymi. Blood 105:31-39
47. Ara T, Itoi M, Kawabata K, Egawa T, Tokoyoda K, et al. 2003. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J. Immunol. 170:4649-55
48. Ueno T, Hara K, Willis MS, Malin MA, Hopken UE, et al. 2 002. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16:205-18
49. Bleul CC, Boehm T. 2000. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30:3371-79
50. Wilkinson B, Owen JJ, Jenkinson EJ. 1999. Factors regulating stem cell recruitment to the fetal thymus. J. Immunol. 162:3873-81
51. Petrie HT. 2003. Cell migration and the control of postnatal T-cell lymphopoiesis in the thymus. Nat. Rev. Immunol. 3:859-66
52. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, et al. 1999. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283:845-48
53. Plotkin J, Prockop SE, Lepique A, Petrie HT. 2003. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171:4521-27
54. Hernandez-Lopez C, Varas A, Sacedon R, Jimenez E, Munoz JJ, et al. 2002. Stromal cell-derived factor 1/CXCR4 signaling is critical for early human T-cell development. Blood 99:546-54
55. Uehara S, Grinberg A, Farber JM, Love PE. 2002. A role for CCR9 in T lymphocyte development and migration. J. Immunol. 168:2811-19
56. Massa S, Balciunaite G, Ceredig R, Rolink AG. 2006. Critical role for c-kit (CD117) in T cell lineage commitment and early thymocyte development in vitro. Eur. J. Immunol. 36:526-32
57. Rodewald HR, Ogawa M, Haller C, Waskow C, DiSanto JP. 1997. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma; chain is essential for repertoire formation. Immunity 6:265-72
58. Bernstein A, Forrester L, Reith AD, Dubreuil P, Rottapel R. 1991. The murine W/c-kit and Steel loci and the control of hematopoiesis. Semin. Hematol. 28:138-42
59. + thymocytes regulate proliferation and cell adhesion. J. Immunol. 172:1099-1108
60. El Andaloussi A, Graves S, Meng F, Mandal M, Mashayekhi M, Aifantis I. 2006. Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus. Nat. Immunol. 7:418-26
61. Allman D, Sambandam A, Kim S, Miller JP, Pagan A, et al. 2003. Thymopoiesis independent of common lymphoid progenitors. Nat. Immunol. 4:168-74
62. Zamisch M, Moore-Scott B, Su DM, Lucas PJ, Manley N, Richie ER. 2005. Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J. Immunol. 174:60-67
63. Misslitz A, Pabst O, Hintzen G, Ohl L, Kremmer E, et al. 2004. Thymic T cell development and progenitor localization depend on CCR7. J. Exp. Med. 200:481-91
64. Mori S, Shortman K, Wu L. 2001. Characterization of thymus-seeding precursor cells from mouse bone marrow. Blood 98:696-704
65. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, et al. 1999. Deficient T cell fate specification in mice with an induced inactivation of Notchl. Immunity 10:547-58
66. Robey E, Chang D, Itano A, Cado D, Alexander H, et al. 1996. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87:483-92
67. Han H, Tanigaki K, Yamamoto N, Kuroda K, Yoshimoto M, et al. 2002. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14:637-45
68. Jaleco AC, Neves H, Hooijberg E, Gameiro P, Clode N, et al. 2001. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194:991-1002
69. Sambandam A, Maillard I, Zediak VP, Xu L, Gerstein RM, et al. 2005. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat. Immunol. 6:663-70
70. Tan JB, Visan I, Yuan JS, Guidos CJ. 2005. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nat. Immunol. 6:671-79
71. Schmitt TM, Zúñiga-Pflücker JC. 2002. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17:749-56
72. + progenitor cells mature to T cells on OP9-DL1 stromal cell line without thymus microenvironment. Blood Cells Mol. Dis. 33:227-32
73. Schmitt TM, Ciofani M, Petrie HT, Zúñiga-Pflücker JC. 2004. Maintenance of T cell specification and differentiation requires recurrent Notch receptor-ligand interactions. J. Exp. Med. 200:469-79
74. Wang H, Pierce J, Spangrude GJ. 2006. Distinct roles of IL-7 and stem cell factor in the OP9-DL1 T cell differentiation culture system. Exp. Hematol. 34:1730-40
75. Jimenez E, Vicente A, Sacedon R, Munoz JJ, Weinmaster G, et al. 2001. Distinct mechanisms contribute to generate and change the CD4:CD8 cell ratio during thymus development: a role for the Notch ligand, Jagged1. J. Immunol. 166:5898-6008
76. de La Coste A, Freitas AA. 2006. Notch signaling: distinct ligands induce specific signals during lymphocyte development and maturation. Immunol. Lett. 102:1-9
77. Lehar SM, Dooley J, Farr AG, Bevan MJ. 2005. Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors. Blood 105:1440-47
78. Santos M, Rio P, Ruiz S, Martinez-Palacio J, Segrelles C, et al. 2005. Altered T cell differentiation and Notch signaling induced by the ectopic expression of keratin K10 in the epithelial cells of the thymus. J. Cell. Biochem. 95:543-58
79. Yan XQ, Sarmiento U, Sun Y, Huang G, Guo J, et al. 2001. A novel Notch ligand, D114, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 98:3793-99
80. Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J. 1997. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol. Cell. Biol. 17:6057-67
81. Felli MP, Maroder M, Mitsiadis TA, Campese AF, Bellavia D, et al. 1999. 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. 11:1017-25
82. Hozumi K, Negishi N, Suzuki D, Abe N, Sotomaru Y, et al. 2004. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat. Immunol. 5:638-44
83. Schmitt TM, Zúñiga-Pflücker JC. 2006. T-cell development, doing it in a dish. Immunol. Rev. 209:95-102
84. +) thymocytes in normal and genetically modified mice. J. Immunol. 154:5103-13
85. Igarashi H, Gregory SC, Yokota T, Sakaguchi N, Kincade PW. 2002. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17:117-30
86. Borghesi L, Aites J, Nelson S, Lefterov P, James P, Gerstein R. 2005. E47 is required for V(D)J recombinase activity in common lymphoid progenitors. J. Exp. Med. 202:1669-77
87. Wilson A, Held W, MacDonald HR. 1994. Two waves of recombinase gene expression in developing thymocytes. J. Exp. Med. 179:1355-60
88. + Pro-T thymocytes. Proc. Natl. Acad. Sci. USA 95:12522-27
89. Livak F, Tourigny M, Schatz DG, Petrie HT. 1999. Characterization of TCR gene rearrangements during adult murine T cell development. J. Immunol. 162:2575-80
90. Durum SK, Candeias S, Nakajima H, Leonard WJ, Baird AM, et al. 1998. Interleukin 7 receptor control of T cell receptor γ gene rearrangement: role of receptor-associated chains and locus accessibility. J. Exp. Med. 188:2233-41
91. Huang J, Durum SK, Muegge K. 2001. Cutting edge: histone acetylation and recombination at the TCR γ locus follows IL-7 induction. J. Immunol. 167:6073-77
92. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, et al. 2001. The IL-7 receptor controls the accessibility of the TCRγ locus by Stat5 and histone acetylation. Immunity 15:813-23
93. Maki K, Sunaga S, Ikuta K. 1996. The V-J recombination of T cell receptor-γ genes is blocked in interleukin-7 receptor-deficient mice. J. Exp. Med. 184:2423-27
94. Malissen M, Pereira P, Gerber DJ, Malissen B, DiSanto JP. 1997. The common cytokine receptor γ chain controls survival of γ/δ T cells. J. Exp. Med. 186:1277-85
95. von Freeden-Jeffry U, Solvason N, Howard M, Murray R. 1997. The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7:147-54
96. -/- mice. Cell 89:1011-19
97. Maraskovsky E, Teepe M, Morrissey PJ, Braddy S, Miller RE, et al. 1996. Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells. J. Immunol. 157:5315-23
98. Montecino-Rodriguez E, Dorshkind K. 1996. Long-term culture of triple-negative thymocytes. J. Immunol. 156:957-62
99. Vissinga CS, Fatur-Saunders DJ, Takei F. 1992. Dual role of IL-7 in the growth and differentiation of immature thymocytes. Exp. Hematol. 20:998-1003
100. Kang J, Coles M, Raulet DH. 1999. Defective development of γ/δ T cells in interleukin 7 receptor-deficient mice is due to impaired expression of T cell receptor γ genes. J. Exp. Med. 190:973-82
101. Kitazawa H, Muegge K, Badolato R, Wang JM, Fogler WE, et al. 1997. IL-7 activates α4β1 integrin in murine thymocytes. J. Immunol. 159:2259-64
102. Munitic I, Williams JA, Yang Y, Dong B, Lucas PJ, et al. 2004. Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis. Blood 104:4165-72
103. Godfrey DI, Zlotnik A, Suda T. 1992. Phenotypic and functional characterization of c-kit expression during intrathymic T cell development. J. Immunol. 149:2281-85
104. Asamoto H, Mandel TE. 1981. Thymus in mice bearing the Steel mutation. Morphologic studies on fetal, neonatal, organ-cultured, and grafted fetal thymus. Lab. Invest. 45:418-26
105. Aiuti A, Tavian M, Cipponi A, Ficara F, Zappone E, et al. 1999. Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors. Eur. J. Immunol. 29:1823-31
106. Zaitseva MB, Lee S, Rabin RL, Tiffany HL, Farber JM, et al. 1998. CXCR4 and CCR5 on human thymocytes: biological function and role in HIV-1 infection. J. Immunol. 161:3103-13
107. Pelletier AJ, van der Laan LJ, Hildbrand P, Siani MA, Thompson DA, et al. 2000. Presentation of chemokine SDF-1α by fibronectin mediates directed migration of T cells. Blood 96:2682-90
108. St-Pierre Y, Hugo P, Legault D, Tremblay P, Potworowski EF. 1996. Modulation of integrin-mediated intercellular adhesion during the interaction of thymocytes with stromal cells expressing VLA-4 and LFA-1 ligands. Eur. J. Immunol. 26:2050-55
109. Taghon TN, David ES, Zúñiga-Pflücker JC, Rothenberg EV. 2005. Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling. Genes Dev. 19:965-78
110. Lee MG, Sharrow SO, Farr AG, Singer A, Udey MC. 1994. Expression of the homotypic adhesion molecule E-cadherin by immature murine thymocytes and thymic epithelial cells. J. Immunol. 152:5653-59
111. Muller KM, Luedecker CJ, Udey MC, Farr AG. 1997. Involvement of E-cadherin in thymus organogenesis and thymocyte maturation. Immunity 6:257-64
112. Prockop SE, Petrie HT. 2004. Regulation of thymus size by competition for stromal niches among early T cell progenitors. J. Immunol. 173:1604-11
113. Marquez C, Trigueros C, Franco JM, Ramiro AR, Carrasco YR, et al. 1998. Identification of a common developmental pathway for thymic natural killer cells and dendritic cells. Blood 91:2760-71
114. Lucas K, Vremec D, Wu L, Shortman K. 1998. A linkage between dendritic cell and T-cell development in the mouse thymus: the capacity of sequential T-cell precursors to form dendritic cells in culture. Dev. Comp. Immunol. 22:339-49
115. Alonso-C LM, Muno z JJ, Zapata AG. 2001. Delineation of intrathymic T, NK, and dendritic cell (DC) progenitors in fetal and adult rats: demonstration of a bipotent T/DC intermediate precursor. J. Immunol. 167:3635-41
116. Carlyle JR, Michie AM, Cho SK, Zúñiga-Pflücker JC. 1998. Natural killer cell development and function precede α β T cell differentiation in mouse fetal thymic ontogeny. J. Immunol. 160:744-53
117. Veinotte LL, Greenwood CP, Mohammadi N, Parachoniak CA, Takei F. 2006. Expression of rearranged TCRγ genes in natural killer cells suggests a minor thymus-dependent pathway of lineage commitment. Blood 107:2673-79
118. Radtke F, Ferrero I, Wilson A, Lees R, Aguet M, MacDonald HR. 2000. Notch I deficiency dissociates the intrathymic development of dendritic cells and T cells. J. Exp. Med. 191:1085-94
119. Uehara S, Hayes SM, Li L, El-Khoury D, Canelles M, et al. 2006. Premature expression of chemokine receptor CCR9 impairs T cell development. J. Immunol. 176:75-84
120. Benz C, Heinzel K, Bleul CC. 2004. Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur. J. Immunol. 34:3652-63
121. Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, et al. 2000. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30:262-71
122. Kim CH, Peius LM, White JR, Broxmeyer HE. 1998. Differential chemotactic behavior of developing T cells in response to thymic chemokines. Blood 91:4434-43
123. Rothenberg EV, Taghon T. 2005. Molecular genetics of T cell development. Annu. Rev. Immunol. 23:601-49
124. Petrie HT, Livak F, Burtrum D, Mazel S. 1995. T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182:121-27
125. Moore TA, Zlotnik A. 1995. T-cell lineage commitment and cytokine responses of thymic progenitors. Blood 86:1850-60
126. Wu L, Li CL, Shortman K. 1996. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype ofthe dendritic cell progeny. J. Exp. Med. 184:903-11
127. Crompton T, Outram SV, Buckland J, Owen MJ. 1997. A transgenic T cell receptor restores thymocyte differentiation in interleukin-7 receptor α chain-deficient mice. Eur. J. Immunol. 27:100-4
128. Muegge K, Vila MP, Durum SK 1993. Interleukin-7: a cofactor for V(D)J rearrangement of the T cell receptor β gene. Science 261:93-95
129. van De Wiele CJ, Marino JH, Murray BW, Vo SS, Whetsell ME, Teague TK. 2004. Thymocytes between the β-selection and positive selection checkpoints are nonresponsive to IL-7 as assessed by STAT-5 phosphorylation. J. Immunol. 172:4235-44
130. Huang J, Garrett KP, Pelayo R, Zúñiga-Pflücker JC, Petrie HT, Kincade PW. 2005. Propensity of adult lymphoid progenitors to progress to DN2/3 stage thymocytes with Notch receptor ligation. J. Immunol. 175:4858-65
131. Balciunaite G, Ceredig R, Fehling HJ, Zúñiga-Pflücker JC, Rolink AG. 2005. The role of Notch and IL-7 signaling in early thymocyte proliferation and differentiation. Eur. J. Immunol. 35:1292-1300
132. Ciofani M, Zúñiga-Pflücker JC. 2005. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nat. Immunol. 6:881-88
133. Huang EY, Gallegos AM, Richards SM, Lehar SM, Bevan MJ. 2003. Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition. J. Immunol. 171:2296-2304
134. Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke F. 2002. Inactivation of Notch1 impairs VDJβ rearrangement and allows pre-TCR-independent survival of early αβ lineage thymocytes. Immunity 16:869-79
135. Moore TA, Zlotnik A. 1997. Differential effects of Flk-2/Flt-3 ligand and stem cell factor on murine thymic progenitor cells. J. Immunol. 158:4187-92
136. Zúñiga-Pflücker JC. 2004. T-cell development made simple. Nat. Rev. Immunol. 4:67-72
137. Wilson A, MacDonald HR. 1995. Expression of genes encoding the pre-TCR and CD3 complex during thymus development. Int. Immunol. 7:1659-64
138. Mombaerts P, Clarke AR, Rudnicki MA, Iacomini J, Itohara S, et al. 1992. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages. Nature 360:225-31
139. Philpott KL, Viney JL, Kay G, Rastan S, Gardiner EM, et al. 1992. Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256:1448-52
140. Shinkai Y, Koyasu S, Nakayama K, Murphy KM, Loh DY, et al. 1993. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259:822-25
141. Dudley EC, Petrie HT, Shah LM, Owen MJ, Hayday AC. 1994. T cell receptor β chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1:83-93
142. Saint-Ruf C, Ungewiss K, Groettrup M, Bruno L, Fehling HJ, von Boehmer H. 1994. Analysis and expression of a cloned pre-T cell receptor gene. Science 266:1208-12
143. Egerton M, Shortman K, Scollay R. 1990. The kinetics of immature murine thymocyte development in vivo. Int. Immunol. 2:501-7
144. Tourigny MR, Mazel S, Burtrum DB, Petrie HT. 1997. T cell receptor (TCR)-β gene recombination: dissociation from cell cycle regulation and developmental progression during T cell ontogeny. J. Exp. Med. 185:1549-56
145. Nikolic-Zugic J, Moore MW, Bevan MJ. 1989. Characterization of the subset of immature thymocytes which can undergo rapid in vitro differentiation. Eur. J. Immunol. 19:649-53
146. Petrie HT, Livak F, Schatz DG, Strasser A, Crispe IN, Shortman K. 1993. Multiple rearrangements in T cell receptor α chain genes maximize the production of useful thymocytes. J. Exp. Med. 178:615-22
147. Fehling HJ, von Boehmer H. 1997. Early αβ T cell development in the thymus of normal and genetically altered mice. Curr. Opin. Immunol. 9:263-75
148. Irving BA, Alt FW, Killeen N. 1998. Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280:905-8
149. Yamasaki S, Ishikawa E, Sakuma M, Ogata K, Sakata-Sogawa K, et al. 2006. Mechanistic basis of pre-T cell receptor-mediated autonomous signaling critical for thymocyte development. Nat. Immunol. 7:67-75
150. Haks MC, Lefebvre JM, Lauritsen JP, Carleton M, Rhodes M, et al. 2005. Attenuation of γδTCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22:595-606
151. Hayes SM, Li L, Love PE. 2005. TCR signal strength influences αβ/γδ lineage fate. Immunity 22:583-93
152. Norment AM, Bogatzki LY, Gantner BN, Bevan MJ. 2000. Murine CCR9, a chemokine receptor for thymus-expressed chemokine that is up-regulated following pre-TCR signaling. J. Immunol. 164:639-48
153. Kim MG, Lee G, Lee SK, Lolkema M, Yim J, et al. 2000. Epithelial cell-specific laminin 5 is required for survival of early thymocytes. J. Immunol. 165:192-201
154. Wadsworth S, Halvorson MJ, Coligan JE. 1992. Developmentally regulated expression of the β4 integrin on immature mouse thymocytes. J. Immunol. 149:421-28
155. Giancotti FG. 1996. Signal transduction by the α6β4 integrin: charting the path between laminin binding and nuclear events. J. Cell Sci. 109:1165-72
156. Murgia C, Blaikie P, Kim N, Dans M, Petrie HT, Giancotti FG. 1998. Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin β4 cytoplasmic domain. EMBO J. 17:3940-51
157. Nikolopoulos SN, Blaikie P, Yoshioka T, Guo W, Giancotti FG. 2004. Integrin β4 signaling promotes tumor angiogenesis. Cancer Cell 6:471-83
158. Cleverley S, Henning S, Cantrell D. 1999. Inhibition of Rho at different stages of thymocyte development gives different perspectives on Rho function. Curr. Biol. 9:657-60
159. Vielkind S, Gallagher-Gambarelli M, Gomez M, Hinton HJ, Cantrell DA. 2005. Integrin regulation by RhoA in thymocytes. J. Immunol. 175:350-57
160. Henning SW, Galandrini R, Hall A, Cantrell DA. 1997. The GTPase Rho has a critical regulatory role in thymus development. EMBO J. 16:2397-407
161. Galandrini R, Henning SW, Cantrell DA. 1997. Different functions of the GTPase Rho in prothymocytes and late pre-T cells. Immunity 7:163-74
162. Savino W, Villa-Verde DM, Lannes-Vieira J. 1993. Extracellular matrix proteins in intrathymic T-cell migration and differentiation? Immunol. Today 14:158-61
163. Magner WJ, Chang AC, Owens J, Hong MJ, Brooks A, Coligan JE. 2000. Aberrant development of thymocytes in mice lacking laminin-2. Dev. Immunol. 7:179-93
164. Gravestein LA, van Ewijk W, Ossendorp F, Borst J. 1996. CD27 cooperates with the pre-T cell receptor in the regulation of murine T cell development. J. Exp. Med. 184:675-85
165. Taghon T, Yui MA, Pant R, Diamond RA, Rothenberg EV. 2006. Developmental and molecular characterization of emerging β- and γδ-selected pre-T cells in the adult mouse thymus. Immunity 24:53-64
166. Giroir BP, Brown T, Beutler B. 1992. Constitutive synthesis of tumor necrosis factor in the thymus. Proc. Natl. Acad. Sci. USA 89:4864-68
167. Hintzen RQ, Lens SM, Koopman G, Pals ST, Spits H, van Lier RA. 1994. CD70 represents the human ligand for CD27. Int. Immunol. 6:477-80
168. Tanigaki K, Tsuji M, Yamamoto N, Han H, Tsukada J, et al. 2004. Regulation of αβ/γδ T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity 20:611-22
169. Ciofani M, Schmitt TM, Ciofani A, Michie AM, Cuburu N, et al. 2004. Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation. J. Immunol. 172:5230-39
170. Voll RE, Jimi E, Phillips RJ, Barber DF, Rincon M, et al. 2000. NF-kappa B activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13:677-89
171. Bevan MJ. 1977. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature 269:417-18
172. β domains controlled by distinct cell populations in the thymus. J. Exp. Med. 170:2165-70
173. 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. 14:207-15
174. Starr TK, Jameson SC, Hogquist KA. 2003. Positive and negative selection of T cells. Annu. Rev. Immunol. 21:139-76
175. Lucas B, Germain RN. 2000. Opening a window on thymic positive selection: developmental changes in the influence of cosignaling by integrins and CD28 on selection events induced by TCR engagement. J. Immunol. 165:1889-95
176. Kishimoto H, Cai Z, Brunmark A, Jackson MR, Peterson PA, Sprent J. 1996. Differing roles for B7 and intercellular adhesion molecule-1 in negative selection of thymocytes. J. Exp. Med. 184:531-37
177. Germain RN. 2002. T-cell development and the CD4-CD8 lineage decision. Nat. Rev. Immunol. 2:309-22
178. + T cells. Immunity 13:59-71
179. Bosselut R, Guinter TI, Sharrow SO, Singer A. 2003. Unraveling a
180. Sarafova SD, Erman B, Yu Q, Van Laethem F, Guinter T, et al. 2005. Modulation of coreceptor transcription during positive selection dictates lineage fate independently of TCR/coreceptor specificity. Immunity 23:75-87
181. Yu Q, Park JH, Doan LL, Erman B, Feigenbaum L, Singer A. 2006. Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. J. Exp. Med. 203:165-75
182. + T cells. J. Exp. Med. 197:475-87
183. Witt CM, Raychaudhuri S, Schaefer B, Chakraborty AK, Robey EA. 2005. Directed migration of positively selected thymocytes visualized in real time. PLoS Biol. 3:e160
184. Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, et al. 2006. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24:165-77
185. Egerton M, Scollay R, Shortman K. 1990. Kinetics of mature T-cell development in the thymus. Proc. Natl. Acad. Sci. USA 87:2579-82
186. Longo DL, Kruisbeek AM, Davis ML, Matis LA. 1985. Bone marrow-derived thymic antigen-presenting cells determine self-recognition of la-restricted T lymphocytes. Proc. Natl. Acad. Sci. USA 82:5900-4
187. Kyewski BA, Fathman CG, Rouse RV. 1986. Intrathymic presentation of circulating non-MHC antigens by medullary dendritic cells. An antigen-dependent microenvironment for T cell differentiation. J. Exp. Med. 163:231-46
188. Sprent J, Gao EK, Webb SR. 1990. T cell reactivity to MHC molecules: immunity versus tolerance. Science 248:1357-63
189. Kyewski BA, Fathman CG, Kaplan HS. 1984. Intrathymic presentation of circulating nonmajor histocompatibility complex antigens. Nature 308:196-99
190. Kyewski B, Derbinski J. 2004. Self-representation in the thymus: an extended view. Nat. Rev. Immunol. 4:688-98
191. Heath WR, Carbone FR. 2001. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19:47-64
192. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, et al. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395-1401
193. Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. 2005. The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227-39
194. Gallegos AM, Bevan MJ. 2006. Central tolerance: good but imperfect. Immunol. Rev. 209:290-96
195. Vacchio MS, Williams JA, Hodes RJ. 2005. A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection. Eur. J. Immunol. 35:418-27
196. + thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus. J. Exp. Med. 186:1911-22
197. Amsen D, Revilla Calvo C, Osborne BA, Kruisbeek AM. 1999. Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4+CD8+ thymocytes. Proc. Natl. Acad. Sci. USA 96:622-27
198. Carlow DA, van Oers NS, Teh SJ, Teh HS. 1992. Deletion of antigen-specific immature thymocytes by dendritic cells requires LFA-1/ICAM interactions. J. Immunol. 148:1595-1603
199. 2+ signal. Biochem. Biophys. Res. Commun. 288:1188-93
200. Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, et al. 2004. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200:493-505
201. Kim CH, Pelus LM, White JR, Applebaum E, Johanson K, Broxmeyer HE. 1998. CK β-11/macrophage inflammatory protein-3 β/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells. J. Immunol. 160:2418-24
202. Campbell JJ, Pan J, Butcher EC. 1999. Cutting edge: developmental switches in chemokine responses during T cell maturation. J. Immunol. 163:2353-57
203. Kwan J, Killeen N. 2004. CCR7 directs the migration of thymocytes into the thymic medulla. J. Immunol. 172:3999-4007
204. Buhlmann JE, Elkin SK, Sharpe AH. 2003. A role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J. Immunol. 170:5421-28
205. Foy TM, Page DM, Waldschmidt TJ, Schoneveld A, Laman JD, et al. 1995. An essential role for gp39, the ligand for CD40, in thymic selection. J. Exp. Med. 182:1377-88
206. + T cells. Eur. J. Immunol. 29:2684-94
207. + stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1:197-205
208. Hancock WW, Sayegh MH, Zheng XG, Peach R, Linsley PS, Turka LA. 1996. Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection. Proc. Natl. Acad. Sci. USA 93:13967-72
209. Nitta T, Nasreen M, Seike T, Goji A, Ohigashi I, et al. 2006. IAN family critically regulates survival and development of T lymphocytes. PLoS Biol. 4:e103
210. Fontenot JD, Rudensky AY. 2005. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6:331-37
211. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. 2006. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7:401-10
212. Tarbell KV, Yamazaki S, Steinman RM. 2006. The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin. Immunol. 18:93-102
213. + regulatory T cells in human thymus. Nature 436:1181-85
214. Jiang Q, Su H, Knudsen G, Helms W, Su L. 2006. Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP. BMC Immunol. 7:6
215. Gabor MJ, Godfrey DI, Scollay R. 1997. Recent thymic emigrants are distinct from most medullary thymocytes. Eur. J. Immunol. 27:2010-15
216. - thymocytes lacking the heat-stable antigen. Cell. Immunol. 117:312-26
217. - thymocytes are functionally immature. J. Immunol. 147:1779-85
218. + single-positive thymocytes requires the thymus to produce long-lived, functional T cells. J. Exp. Med. 181:235-45
219. Dyall R, Nikolic-Zugic J. 1999. The final maturation of at least some single-positive CD4(hi) thymocytes does not require T cell receptor-major histocompatibility complex contact. J. Exp. Med. 190:757-64
220. Nikolic-Zugic J, Bevan MJ. 1990. Functional and phenotypic delineation of two subsets of CD4 single positive cells in the thymus. Int. Immunol. 2:135-41
221. Uldrich AP, Berzins SP, Malin MA, Bouillet P, Strasser A, et al. 2006. Antigen challenge inhibits thymic emigration. J. Immunol. 176:4553-61
222. + regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22:531-62
223. Feng C, Woodside KJ, Vance BA, El-Khoury D, Canelles M, et al. 2002. A potential role for CD69 in thymocyte emigration. Int. Immunol. 14:535-44
224. Nakayama T, Kasprowicz DJ, Yamashita M, Schubert LA, Gillard G, et al. 2002. The generation of mature, single-positive thymocytes in vivo is dysregulated by CD69 blockade or overexpression. J. Immunol. 168:87-94
225. Lauzurica P, Sancho D, Torres M, Albella B, Marazuela M, et al. 2000. Phenotypic and functional characteristics of hematopoietic cell lineages in CD69-deficient mice. Blood 95:2312-20
226. Yagi H, Kamba R, Chiba K, Soga H, Yaguchi K, et al. 2000. Immunosuppressant FTY720 inhibits thymocyte emigration. Eur. J. Immunol. 30:1435-44
227. Rosen H, Alfonso C, Surh CD, McHeyzer-Williams MG. 2003. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc. Natl. Acad. Sci. USA 100:10907-12
228. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, et al. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355-60
229. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, et al. 2006. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P(1) antagonist in vivo. Nat. Chem. Biol. 2:434-41
230. Chaffin KE, Perlmutter RM. 1991. A pertussis toxin-sensitive process controls thymocyte emigration. Eur. J. Immunol. 21:2565-73
231. Poznansky MC, Olszak IT, Evans RH, Wang Z, Foxall RB, et al. 2002. Thymocyte emigration is mediated by active movement away from stroma-derived factors. J. Clin. Invest. 109:1101-10
232. Vianello F, Kraft P, Mok YT, Hart WK, White N, Poznansky MC. 2005. A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cells from the fetal thymus. J. Immunol. 175:5115-25