IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease
Katia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, Antonios O. Aliprantis
Katia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, Antonios O. Aliprantis
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Research Article Immunology

IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease

Abstract

Systemic sclerosis (SSc) is a potentially fatal autoimmune disorder with limited therapeutic options. Sclerodermatous graft versus host disease (sclGvHD), induced by transfer of B10.D2 splenocytes into BALB/c Rag2–/– mice, models an inflammatory subset of SSc characterized by a prominent IL13-induced gene expression signature in the skin. Host mice deficient in IL4RA, a subunit of the type II IL4/IL13 receptor, are protected from sclGvHD. While IL4RA has a well-established role in Th2 differentiation and alternative macrophage activation, we report here a previously unappreciated function for IL4RA in lymphatic endothelial cells (LECs): regulation of activated T cell egress. Seven days after splenocyte transfer, Il4ra–/– hosts had increased numbers of activated graft CD4+ T cells in skin draining lymph nodes (dLNs) but fewer T cells in efferent lymph, blood, and skin. Sphingosine-1 phosphate (S1P), master regulator of lymphocyte egress from LNs, was lower in dLNs of Il4ra–/– hosts with a corresponding decrease of S1P kinase 1 (Sphk1) expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4+ T cells from dLNs of Il4ra–/– sclGvHD mice restored clinical GvHD in secondary Il4ra–/– recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.

Authors

Katia Urso, David Alvarez, Viviana Cremasco, Kelly Tsang, Angelo Grauel, Robert Lafyatis, Ulrich H. von Andrian, Joerg Ermann, Antonios O. Aliprantis

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Figure 4

dLNs isolated from 7d-sclGvHD Il4ra–/– mice display a defect in S1P pathway.

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dLNs isolated from 7d-sclGvHD Il4ra–/– mice display a defect in S1P path...
(A and B) Representative IHC of CD3 in back skin sections (A) and number of CD4+ T cells isolated from dLNs (B) of 7d-sclGvHD mice treated with 3 mg/kg FTY720 or saline for 6 days (n = 9–10 per group, ***P < 0.001, Student’s t test; 10×. Scale bar: 200 μm). (C) Relative S1P concentration (S1P) in dLN media prepared from 7d-sclGvHD and 7d-sclGvHD Il4ra–/– mice (n = 9–11 per group, ***P < 0.001, Student’s t test). (D) Representative plot and MFI for S1PR1 surface staining of CD4+ T cells isolated from dLNs of 7d-sclGvHD and 7d-sclGvHD Il4ra–/– mice (n = 5 per group). Blood CD4+ T cells are used as negative control. (E) qPCR measuring Sphk1 expression in cDNA prepared from the dLNs of 7d-sclGvHD and 7d-sclGvHD Il4ra–/– mice (n = 10 per group, ****P < 0.0001, Student’s t test).