A model for switch-like phenomena in biological systems

Testorf, Martin F.; Karlsson, Annika M.; Svensson, Samuel; Öberg, P Åke; Lundström, Ingemar

doi:10.1016/s0301-4622(01)00231-9

Cited by 6 publications

(2 citation statements)

References 14 publications

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“…A threshold of S1P receptor activation thus acts as a biological on switch at low nanomolar concentrations of agonist. This is seen in many agonist-driven processes such as threshold T cell receptor occupancy needed to trigger clonal expansion (62) or activation of responses to serotonin or ryanodine (63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist

Rosen

Alfonso

Surh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

101

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Only a small number of T cells generated in the thymus each day are selected to replenish the peripheral T cell pool. Much is known about thymic selection; however, little is known of the mechanisms regulating medullary maturation and the release of mature T cells into the blood. Here we demonstrate a rapid acceleration of medullary thymocyte phenotypic maturation through loss of CD69 induced by sphingosine 1-phosphate (S1P) receptor agonist. Low nanomolar agonist concentrations selectively induce changes in CD69 int CD62L high single positive T cells, resulting in down-modulation of CD69 within 2 h. While CD69 loss is accelerated, egress of mature T cells into blood is inhibited >95% within 2 h. Both processes exhibit parallel sensitivities and dose-responses. Together, these data reveal a potent means for rapidly regulating thymic export where S1P receptor agonism alters both phenotypic maturation and egress of thymocytes into blood during late thymic maturation. The S1P system is now shown to acutely regulate both thymic and lymph node egress. Inhibition of lymphocyte egress from thymus and lymph node can contribute synergistically to clinically useful immunosupression by disrupting recirculation of peripheral T cells. S phingosine 1-phosphate (S1P) receptor agonists, such as the phosphate-ester metabolite of FTY720 (1, 2), are clinically useful immunosuppressants for transplantation rejection (3) and have recently been shown to regulate egress of naïve lymphocytes (4) and both CD4 (5) and CD8 (6) effector cells by retention of lymphocytes on the abluminal side of sinus-lining endothelium in lymph nodes but not spleen (4, 7). Long-term studies have also demonstrated effects on the emigration of thymocytes from thymus into blood and secondary lymphoid organs (8), suggesting that an important step in thymic egress is also affected. FTY720 and its chiral analog 2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol [AAL-(R)] are full agonists for four of five G protein-coupled receptors for S1P. Originally described as endothelial differentiation genes, or edg receptors, five cloned G protein-coupled high-affinity receptors (9) have been described for S1P that show low nanomolar binding affinities (10-14). They are closely related structurally to the receptors edg2͞lpa1, edg4͞lpa2, and edg7͞lpa3 for lysophophatidic acid. They are expressed on endothelial cells (S1P 1 , S1P 3 ), and mRNA can be detected in lymphocytes (S1P 4 , S1P 5 ) (15, 16) and on vascular smooth muscle and myocardium (S1P 2 and S1P 1 ). Some investigators have suggested that S1P 1 is also expressed in lymphocytes, although the presence of active receptor on uncultured lymphocytes remains controversial (17)(18)(19). Of these receptors, only S1P 2 is not activated by the phosphoryl metabolite of FTY720 (1). S1P 1 , S1P 3 , S1P 5 , and S1P 4 receptors activate multiple cellular responses, through pertussis toxin (PTX)-sensitive i.e., G icoupled events, and PTX-independent transduction steps (activation of rac and rho small GTP-binding proteins) (20-23). ...

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Section: Discussionmentioning

confidence: 99%

Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist

Rosen

Alfonso

Surh

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

101

View full text Add to dashboard Cite

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“…The variation in the gap with the variable parameters is discussed in some previous studies [37,36,40]. According to these studies, the parameters can actually affect the gap size and the joint state.…”

Section: The Influence Of the Parametersmentioning

confidence: 99%