FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues.
Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3(+) T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3(+) T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4(+) T cells as well as unique to the FoxP3(+) cell lineage. In the thymus, precursors of FoxP3(+) cells undergo the first trafficking receptor switch (CCR8/CCR9-->CXCR4-->CCR7), generating mostly homogeneous CD62L(+)CCR7(+)CXCR4(low)FoxP3(+) T cells. CXCR4 expression is regained in FoxP3(+) thymic emigrants in the periphery. Consistent with this switch, recent FoxP3(+) thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3(+) thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3(+) T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3(+) and FoxP3(-) T cell populations is that FoxP3(+) T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3(-) T cells, generating FoxP3(+) T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.
Lee
Jee H
JH
Department of Comparative Pathobiology, Laboratory of Immunology and Hematopoiesis, Purdue Cancer Center, and Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
Kang
Seung G
SG
Kim
Chang H
CH
D000818:Animals; D002465:Cell Movement; D051858:Forkhead Transcription Factors / Q000032:analysis*; D019041:L-Selectin / Q000032:analysis; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
C514936:CXCR4 protein, mouse; C515371:Ccr7 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D016201:Receptors, Lymphocyte Homing; D019041:L-Selectin