CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance.
Immature CD4+CD8+ thymocytes, which are generated in the thymic cortex, are induced upon positive selection to differentiate into mature T lymphocytes and relocate to the thymic medulla. It was recently shown that a chemokine signal via CCR7 is essential for the cortex-to-medulla migration of positively selected thymocytes in the thymus. However, the role of the cortex-to-medulla migration in T cell development and selection has remained unclear. The present study shows that the developmental kinetics and the thymic export of mature thymocytes were undisturbed in adult mice lacking CCR7 or its ligands (CCR7L). The inhibition of sphingosine-1-phosphate-mediated lymphocyte egress from the thymus led to the accumulation of mature thymocytes in the cortex of CCR7- or CCR7L-deficient mice, unlike the accumulation in the medulla of normal mice, thereby suggesting that mature thymocytes may be exported directly from the cortex in the absence of CCR7 signals. However, the thymocytes that were generated in the absence of CCR7 or CCR7L were potent in causing autoimmune dacryoadenitis and sialadenitis in mice and were thus incapable of establishing central tolerance to organ-specific antigens. These results indicate that CCR7-mediated cortex-to-medulla migration of thymocytes is essential for establishing central tolerance rather than for supporting the maturation or export of thymocytes.
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
Hirotsugu
H
Kurobe
Cunlan
C
Liu
Tomoo
T
Ueno
Fumi
F
Saito
Izumi
I
Ohigashi
Natalie
N
Seach
Rieko
R
Arakaki
Yoshio
Y
Hayashi
Tetsuya
T
Kitagawa
Martin
M
Lipp
Richard L
RL
Boyd
Yousuke
Y
Takahama
D000818:Animals; D015551:Autoimmunity; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D003713:Dendritic Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D007108:Immune Tolerance; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
C515371:Ccr7 protein, mouse; D008246:Lysophospholipids; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C060506:sphingosine 1-phosphate; D013110:Sphingosine