IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease.
basic_science · Level V
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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 <i>Rag2<sup>-/-</sup></i> 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, <i>Il4ra<sup>-/-</sup></i> hosts had increased numbers of activated graft CD4<sup>+</sup> 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 <i>Il4ra<sup>-/-</sup></i> hosts with a corresponding decrease of S1P kinase 1 (<i>Sphk1</i>) expression in LECs. Bypassing the efferent lymphatics via i.v. injection of CD4<sup>+</sup> T cells from dLNs of <i>Il4ra<sup>-/-</sup></i> sclGvHD mice restored clinical GvHD in secondary <i>Il4ra<sup>-/-</sup></i> recipients. These results identify a role for IL4RA and suggest that modulation of lymphocyte egress from LNs may be effective in SSc and GvHD.