Journal Article

Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1

Allende, Maria L., Proia, Richard L., Lesneski, Matthew J., Cinamon, Guy, Xu, Ying, Brinkmann, Volker, Lo, Charles G., Cyster, Jason G., Matloubian, Mehrdad

2004

Overview

Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors 1 , 2 , 3 , 4 . However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P 1 ; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P 1 in T and B cells for lymphoid organ egress. Furthermore, S1P 1 -dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P 1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P 1 , creating a temporary pharmacological S1P 1 -null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P 1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Adoptive Transfer / Animals / Biological and medical sciences / Cell Movement - drug effects / Chemotaxis - drug effects / Chimera - metabolism / Down-Regulation - drug effects / Edg1 protein / Emigration / Fingolimod Hydrochloride / FTY720 / Fundamental and applied biological sciences. Psychology / Fundamental immunology / Gene Deletion / Humanities and Social Sciences / Immunobiology / Immunology / letter / Lymphocyte Activation - drug effects / Lymphocyte receptors / Lymphocytes / Lymphocytes - cytology / Lymphocytes - drug effects / Lymphocytes - metabolism / Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation / Lymphoid Tissue - cytology / Lymphoid Tissue - drug effects / Lymphoid Tissue - immunology / Lysophospholipids / Mice / Mice, Knockout / multidisciplinary / Organs / Propylene Glycols - pharmacology / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Receptors, Lysophospholipid / Science / Science (multidisciplinary) / Sphingosine - analogs & derivatives / Sphingosine - pharmacology / sphingosine 1-phosphate receptors / T cell receptors / Thymus Gland - cytology / Thymus Gland - drug effects / Thymus Gland - immunology