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Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor

Jia-Jun Liao^*,1, Mei-Chuan Huang^*,1, Katharine Fast^*, Katherine Gundling^*, Mahesh Yadav^*, James R. Van Brocklyn, Matthias R. Wabl and Edward J. Goetzl^*,,2

^* Department of Medicine and

Department of Microbiology-Immunology, University of California San Francisco, San Francisco, California, USA; and

Department of Pathology, The Ohio State University, Columbus, Ohio, USA

²Correspondence: University of California Medical Center, Rm. UB8B, UCSF Box 0711, 533 Parnassus at 4th Ave., San Francisco, CA 94143-0711, USA. E-mail: edward.goetzl{at}ucsf.edu

Anti-lymphocyte antibodies (Abs) that suppress T-cell chemotactic and other responses to sphingosine 1-phosphate (S1P), but not to chemokines, were found in a lymphopenic patient with recurrent infections. Lymphocyte type 1 S1P receptor (S1P₁) that transduces S1P chemotactic stimulation was recognized by patient Abs in Western blots of T cells, S1P₁ transfectants, and S1P₁-hemagglutinin purified by monoclonal anti-hemagglutinin Ab absorption. The amino terminus of S1P₁, but not any extracellular loop, prevented anti-S1P₁ Ab suppression of S1P₁ signaling and T-cell chemotaxis to S1P. Human purified anti-S1P₁ Abs decreased mouse blood lymphocyte levels by a mean of 72%, suppressed mouse T-cell chemotaxis to S1P in vivo, and significantly reduced the severity of dextran sodium sulfate-induced colitis in mice. Human Abs to the amino terminus of S1P₁ suppress T-cell trafficking sufficiently to impair host defense and provide therapeutic immunosuppression.—Liao, J.-J., Huang, M.-C., Fast, K., Gundling, K., Yadav, M., Van Brocklyn, J. R., Wabl, M. R., Goetzl, E. J. Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor.

Key Words: inflammation • chemotaxis • sphingolipid • G protein- coupled