Interleukin-4 (IL-4) maintains lymphocyte-stromal cell axis in peripheral lymph nodes

Abstract

Abstract Interleukin-4 (IL-4) is a critical cytokine in the differentiation of Th2 cells, B-cells, and antibody isotype switching. Despite the myriad of functions known to be mediated by IL-4, its role in the spatial organization of lymph node compartments is not well understood. Our studies demonstrate that IL-4 is vital for proper positioning of B cell, T cell and CD11c+ dendritic cells in lymph nodes in steady state, and that the lack of IL-4 and IL-4 receptor (IL-4Rα) correlates with a diminished immune response to Schistosoma mansoni antigens. The absence of IL4 and IL-4R resulted in decreased germinal center (GC) formation, T follicular helper (Tfh) and plasma cells expansion in peripheral lymph nodes in response to this Th2 polarizing antigen, but not to Th1 polarizing Toxoplasma gondii antigens. Stromal cell populations are known to support lymphocyte organization and function within secondary lymphoid tissues. Importantly, we observed a marked disorganization of follicular dendritic cells (FDCs), CD31+ lymphatic, and blood endothelial cells in mice lacking IL4R, suggesting that the lymphocyte-stromal cell axis is maintained by IL-4. Our study also shows that absence of IL-4Rα correlates with significant down-regulation of Lymphotoxin-beta (LTβ) and Lymphotoxin alpha (LTα) gene expression, which is vital for the development of specific stromal populations. Altogether, our results reveal a previously unexplored role of IL-4 in the maintenance of peripheral lymphoid organ microenvironments during an immune challenge as well as in homeostasis.