一项可能帮助移植患者设计免疫抑制药物的新研究发现，一个帮助新的免疫细胞从脾脏和淋巴结进入身体的循环系统的强有力的信号发生分子有两个不同的来源。统称为淋巴细胞的免疫系统T细胞、B细胞和自然杀伤细胞在胸腺、脾脏和淋巴结中发育后进入血液和淋巴循环。一个叫S1P的分子帮助淋巴细胞进入循环，是目前正在临床试验的免疫抑制和自身免疫药物的靶标。Rajita Pappu和同事现在揭示，帮助淋巴细胞进入血液的S1P分子来自红血细胞，而帮助淋巴细胞进入淋巴系统的S1P另有来源。这些供给使淋巴细胞跟随一个淋巴组织和两个循环系统之间的梯度。该发现也许能帮助改进免疫抑制和S1P路径激活的方法。
Published Online March 15, 2007
Science DOI: 10.1126/science.1139221
Science Express Index
Submitted on December 22, 2007
Accepted on March 2, 2007
Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate
Rajita Pappu 1, Susan R. Schwab 2, Ivo Cornelissen 1, João P. Pereira 2, Jean B. Regard 1, Ying Xu 2, Eric Camerer 1, Yao-Wu Zheng 1, Yong Huang 3, Jason G. Cyster 2*, Shaun R. Coughlin 1*
1 Cardiovascular Research Institute, University of California San Francisco, 600 16th Street S472D, San Francisco, CA 94143-2240, USA.
2 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0414, USA.
3 Drug Studies Unit, Department of Biopharmaceutical Sciences, University of California San Francisco, 296 Lawrence Street, San Francisco, CA 94143-0446, USA.
* To whom correspondence should be addressed.
Jason G. Cyster , E-mail: Jason.Cyster@ucsf.edu
Shaun R. Coughlin , E-mail: Shaun.Coughlin@ucsf.edu
Lymphocytes require sphingosine-1-phosphate (S1P)-receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. Using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.
