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. 2017 Feb 10;8:113. doi: 10.3389/fimmu.2017.00113

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Copyright © 2017 Honke, Shaabani, Teijaro, Christen, Hardt, Bezgovsek, Lang and Lang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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FTY720 prevents viral transfer to lymph nodes and thereby inhibits the onset of diabetes. (A) C57BL/6 wild-type (WT) mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 or were left untreated. Mice were infected intravenously (i.v.) or subcutaneously (s.c.) with 20 plaque-forming units (PFUs) of lymphocytic choriomeningitis virus strain WE (LCMV-WE). Viral titer was measured in the spleen, inguinal lymph nodes (iLNs) and liver on day 3 (d3; i.v.) or day 6 (d6; s.c.) after infection (n = 6; pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720. (B) C57BL/6 WT mice were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or were left untreated. CD11c⁺ cells in the spleen, iLNs, and blood were counted on day 0 (n = 6, pooled from two experiments). Black column = WT untreated; white column = WT + FTY720. (C,D) C57BL/6 WT mice were treated daily with FTY720 (1 mg/kg bw) starting on day −2 or were left untreated. Mice were infected s.c. with 20 PFU LCMV-WE. On day 12, total and LCMV-specific CD8⁺ T cells were counted in the spleen (C) and iLNs (D) (n = 6, pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720. (E,F) Transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) under control of the rat insulin promoter (RIP-GP) were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or were left untreated. Mice were intravenously or subcutaneously infected with 20 PFU LCMV-WE. Onset of diabetes was measured (E) i.v., n = 6–8, pooled from two experiments; (F) s.c., n = 5–6, pooled from two experiments. Black squares = RIP-GP LCMV; white squares = RIP-GP LCMV + FTY720. (G) C57BL/6 WT mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 or 3 of infection or left untreated. Mice were infected intravenously (i.v.) with 20 PFU of LCMV-WE. On day 12, tetramer (Tet) GP33-specific CD8⁺ T cells in iLNs were counted by flow cytometry (n = 8, pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720 (starting day −2); red column = LCMV + FTY720 (starting d3). (H) Transgenic mice expressing the LCMV glycoprotein (GP) under control of the rat insulin promoter (RIP-GP) were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or 3 of infection or were left untreated. Mice were intravenously infected with 20 PFU LCMV-WE. Onset of diabetes was measured (n = 6, pooled from two experiments). Black squares = RIP-GP LCMV; white squares = RIP-GP LCMV + FTY720 day −2; red squares = RIP-GP LCMV + FTY d3. (I) C57BL/6 WT mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 till day 3, from day 3 till day 8, or day 2 till day 8 of infection or left untreated. Mice were infected intravenously (i.v.) with 20 PFU of LCMV-WE. On day 9, tetramer (Tet) GP33-specific CD8⁺ T cells in iLNs were counted by flow cytometry (n = 6, pooled from two experiments). Black column = LCMV; gray column = LCMV + FTY720 (starting day −2 till day 3); red column = LCMV + FTY720 (starting day 3 till day 8); white column = LCMV + FTY720 (starting day −2 till day 8). Statistical significance was set at the level of P < 0.05 and was determined by Student’s t-test (A–D,G,I) or log-rank (Mantel–Cox) test (E,F,H). n.s., not significant; *P < 0.5; **P < 0.01; ***P < 0.001.

FTY720 prevents viral transfer to lymph nodes and thereby inhibits the onset of diabetes. (A) C57BL/6 wild-type (WT) mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 or were left untreated. Mice were infected intravenously (i.v.) or subcutaneously (s.c.) with 20 plaque-forming units (PFUs) of lymphocytic choriomeningitis virus strain WE (LCMV-WE). Viral titer was measured in the spleen, inguinal lymph nodes (iLNs) and liver on day 3 (d3; i.v.) or day 6 (d6; s.c.) after infection (n = 6; pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720. (B) C57BL/6 WT mice were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or were left untreated. CD11c⁺ cells in the spleen, iLNs, and blood were counted on day 0 (n = 6, pooled from two experiments). Black column = WT untreated; white column = WT + FTY720. (C,D) C57BL/6 WT mice were treated daily with FTY720 (1 mg/kg bw) starting on day −2 or were left untreated. Mice were infected s.c. with 20 PFU LCMV-WE. On day 12, total and LCMV-specific CD8⁺ T cells were counted in the spleen (C) and iLNs (D) (n = 6, pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720. (E,F) Transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) under control of the rat insulin promoter (RIP-GP) were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or were left untreated. Mice were intravenously or subcutaneously infected with 20 PFU LCMV-WE. Onset of diabetes was measured (E) i.v., n = 6–8, pooled from two experiments; (F) s.c., n = 5–6, pooled from two experiments. Black squares = RIP-GP LCMV; white squares = RIP-GP LCMV + FTY720. (G) C57BL/6 WT mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 or 3 of infection or left untreated. Mice were infected intravenously (i.v.) with 20 PFU of LCMV-WE. On day 12, tetramer (Tet) GP33-specific CD8⁺ T cells in iLNs were counted by flow cytometry (n = 8, pooled from two experiments). Black column = LCMV; white column = LCMV + FTY720 (starting day −2); red column = LCMV + FTY720 (starting d3). (H) Transgenic mice expressing the LCMV glycoprotein (GP) under control of the rat insulin promoter (RIP-GP) were treated daily with FTY720 (1 mg/kg bw) starting from day −2 or 3 of infection or were left untreated. Mice were intravenously infected with 20 PFU LCMV-WE. Onset of diabetes was measured (n = 6, pooled from two experiments). Black squares = RIP-GP LCMV; white squares = RIP-GP LCMV + FTY720 day −2; red squares = RIP-GP LCMV + FTY d3. (I) C57BL/6 WT mice were treated daily with a sphingosine-1-phosphate antagonist [FTY720; 1 mg/kg body weight (bw)] starting from day −2 till day 3, from day 3 till day 8, or day 2 till day 8 of infection or left untreated. Mice were infected intravenously (i.v.) with 20 PFU of LCMV-WE. On day 9, tetramer (Tet) GP33-specific CD8⁺ T cells in iLNs were counted by flow cytometry (n = 6, pooled from two experiments). Black column = LCMV; gray column = LCMV + FTY720 (starting day −2 till day 3); red column = LCMV + FTY720 (starting day 3 till day 8); white column = LCMV + FTY720 (starting day −2 till day 8). Statistical significance was set at the level of P < 0.05 and was determined by Student’s t-test (A–D,G,I) or log-rank (Mantel–Cox) test (E,F,H). n.s., not significant; *P < 0.5; **P < 0.01; ***P < 0.001.