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 6

Transfer of sclGvHD-activated T cells into the blood of sclGvHD Il4ra–/– mice restores disease.

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Transfer of sclGvHD-activated T cells into the blood of sclGvHD Il4ra–/–...
(A–E) Clinical and pathological evaluation of sclGvHD or sclGvHD Il4ra–/– mice, or sclGvHD Il4ra–/– mice that received an additional i.v. injection of CD4+ cells from either B10.D2 mice (Tnaive cells green) or 7d-sclGvHD Il4ra–/– mice (TEM cells, blue). n = 11 for Tnaive-sclGvHD Il4ra–/–, n = 15 for TEM-sclGvHD Il4ra–/–. (A) Kaplan-Meier survival curve showing the % of mice without alopecia (i.e., a clinical score < 2), P = 0.0386, Mantel-Cox test for survival curves. (B) Clinical scores on day 42, **P < 0.01, ***P < 0.001, one-way ANOVA, Kruskal-Wallis test for comparing ranks. (C and D) IHC staining for CD3 (Scale bar: 200 μm) of histological sections of back skin prepared at sacrifice and cell number quantification, *P < 0.05, **P < 0.01, one-way ANOVA followed by Bonferroni post-test. (E) Masson’s Trichrome stain of histological sections of back skin prepared at sacrifice. Lower and upper panel show 2 different mice. Scale bar: 200 μm.