FTY720 suppresses CD4+CD44highCD62L- effector memory T cell-mediated colitis.
FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD4+ T cells (TEM cells; CD45RB(low)CD44(high)CD62L-) into severe combined immunodeficiency (SCID) mice and suppresses interferon-gamma, interleukin-2, and tumor necrosis factor-alpha production by LP CD4+ T cells. The numbers of spleen, peripheral blood, mesenteric lymph node, and LP CD4+ T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD4+ TEM cells as well as splenic CD4+CD45RBhigh T cells expressed several spingosine-1-phosphate receptors that are targets for FTY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD4+CD45RBhigh T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases.
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
R
R
Fujii
T
T
Kanai
Y
Y
Nemoto
S
S
Makita
S
S
Oshima
R
R
Okamoto
K
K
Tsuchiya
T
T
Totsuka
M
M
Watanabe
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D003092:Colitis / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D000068876:Fingolimod Hydrochloride; D018960:Hyaluronan Receptors / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000276:immunology; D019041:L-Selectin / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011409:Propylene Glycols / Q000008:administration & dosage*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D015704:CD4 Antigens; D018960:Hyaluronan Receptors; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011409:Propylene Glycols; D019041:L-Selectin; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine