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Th17 Augmentation in OTII TCR Plus T Cell-Selective Type 1 Sphingosine 1-Phosphate Receptor Double Transgenic Mice¹

Department of Medicine and Department of Microbiology-Immunology, University of California, San Francisco, CA 94143

Sphingosine 1-phosphate (S1P) in blood and lymph controls lymphoid traffic and tissue migration of T cells through signals from the type 1 S1PR (S1P₁), but less is known of effects of the S1P-S1P₁ axis on nonmigration functions of T cells. CD4 T cells from a double transgenic (DTG) mouse express OTII TCRs specific for OVA peptide 323–339 (OVA) and a high level of transgenic S1P₁, resistant to suppression by T cell activation. OVA-activated DTG CD4 T cells respond as expected to S1P by chemotactic migration and reduction in secretion of IFN-. In addition, DTG CD4 T cells stimulated by OVA secrete a mean of 2.5-fold more IL-17 than those from OTII single transgenic mice with concomitantly higher levels of mRNA encoding IL-17 by real-time PCR and of CD4 T cells with intracellular IL-17 detected by ELISPOT assays. OVA challenge of s.c. air pockets elicited influx of more OTII TCR-positive T cells producing a higher level of IL-17 in DTG mice than OTII control mice. Augmentation of the number and activity of Th17 cells by the S1P-S1P₁ axis may thus enhance host defense against microbes and in other settings increase host susceptibility to autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 HL31809.

² Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California Medical Center, Room UB8B, UC Box 0711, 533 Parnassus at 4th Avenue, San Francisco, CA 94143-0711. E-mail address: edward.goetzl{at}ucsf.edu

³ Abbreviations used in this paper: S1P, sphingosine 1-phosphate; S1P₁, type 1 S1P G protein-coupled receptor; WT, wild type; TG, transgenic; DTG, double TG; DTH, delayed-type hypersensitivity; STG, single TG; TNP, trinitrophenol; KLH, keyhole limpet hemocyanin.