Title:
Distribution and Function of IL-7-Producing Cells in Lymphoid Organs

Koichi Ikuta, M.D., Ph.D.
Professor
Laboratory of Biological Protection, Institute for Virus Research, Kyoto University

Abstract:
Interleukin-7 (IL-7) is a cytokine crucial for development and maintenance of lymphocytes. However, how IL-7-expressing cells are distributed in lymphoid organs is not well known. To address this question, we established and analyzed IL-7-GFP knock-in mice. Thymic epithelial cells (TECs) expressed high GFP levels in the cortex and medulla. Thymic mesenchymal cells also expressed GFP. In bone marrow, high levels of GFP were detected in many VCAM-1⁺mesenchymal stromal cells and in some VCAM-1 – cells. Moreover, we detected GFP expression in fibroblastic reticular cells in the T-cell zone and cortical ridge of lymph nodes. Remarkably, lymphatic endothelial cells (LECs) expressed GFP at high levels within the lymph node medulla, skin epidermis and intestinal tissues. Furthermore, GFP is expressed in a subpopulation of intestinal epithelial cells. Overall, IL-7-GFP knock-in mice serve as a unique and powerful tool to examine the identity and distribution of IL-7-expressing cells in vivo.

Next, we address the question on the local function of IL-7 produced by each cell type in vivo. We established IL-7-floxed (IL-7^f) mice and first crossed with FoxN1-Cre Tg mice to obtain the conditional knockout mice deficient in IL-7 production from TECs. FoxN1-Cre x IL-7^f/f mice showed 15-fold reduced numbers of thymocytes compared with control mice, suggesting that IL-7 produced from TECs plays a major role in proliferation and survival of thymocytes. Next, we crossed the IL7-floxed mice with albumin (Alb)-Cre Tg mice to obtain the mice deficient in IL-7 production from hepatocytes. Alb-Cre x IL-7^f/f mice showed moderately reduced numbers of NKT and T cells in adult liver. In addition, B cell development is partially impaired in perinatal liver of Alb-Cre x IL-7^f/f mice. These results demonstrate that hepatocyte-derived IL-7 plays an indispensable role in maintenance of NKT and T cells in adult liver and development of B cells in perinatal liver and suggests that hepatocytes provide a unique IL-7 niche for intrahepatic lymphocytes.