UCSF

Immune cells require numerous growth and survival factors during development in central lymphoid organs as well as in the periphery. Amongst these factors, interleukin-7 (IL-7) plays a central role and is required for T cell homeostasis and function in both health and disease (e.g., HIV disease). Understanding the cellular source(s) of such factors, the conditions controlling their regulated expression, and their mechanism of action on target cells is critical to therapeutic application in humans. Due to low expression levels and poor reagent availability, it has proven difficult to comprehensively describe the cellular sources of IL-7. We have accordingly generated mice in which eGFP is expressed from the IL-7 locus under the control of the endogenous promoter. We report that substantial Il-7 is produced by lymphatic endothelial cells (LECs) distributed throughout the systemic lymphatic vasculature, including the lymph node (LN) sinuses, and that STAT5 phosphorylation (pSTAT5) is increased in lymphocytes harvested from efferent lymphatics. We further show that Il-7 is increased in stromal cell subsets within the LN during acute lymphocyte blockade and that this effect is not driven by myeloid Il-7 expression. Our data support recent findings that lymphocyte homeostasis requires access to secondary lymphoid organs (SLOs) but introduce LECs as a significant in vivo source of potentially regulatable IL-7 that bathes trafficking immune cells under both resting and lymphopenic conditions. Finally, these data are not consistent with the concept of a static peripheral IL-7 pool and confirm the existence of a feedback loop that increases IL-7 availability during periods of lymphopenia. The Il-7 reporter model described here offers a new and exciting tool for understanding how this cytokine influences peripheral immune cell function.