Cytokines and T Cell Development

Basic Sciences

Investigators

Linked publications & trials

Abstract

We published our finding that a major activity of IL-7 was through destabilization of the cell cycle inhibitor p27kip1. This explained how IL-7 induced cell division in T cells. We published our findings concerning the role of the intracellular domain of IL-7 receptor. This showed that the intracellular domain of other cytokine receptors can mimic some functions of the IL-7 receptor in T and B cell development. However one unique function of IL-7 receptor is the induction of TCR gamma gene rearrangement. We published our findings that pharmacological treatment with IL-7 induces a broad hematological stimulation, including myelopoiesis and erythropoiesis. This showed beneficial effects of IL-7 treatment beyond the expected effects on lymphopoiesis. Although IL-7 is essential for normal T cell development and maintenance, it has not been determined which cells actually produce the IL-7 protein because it is below the level of detection by immunohistochemistry. We produced mice with a marker knocked into the IL-7 locus that permitted visualizing the producing cells. This showed an extensive reticular network of IL-7-containing processes in thymus and bone marrow and the study is submitted for publication. We showed that the development of regulatory T cells requires stimulation by either IL-7 or TSLP and have submitted that study for publication. For homeostatic survival, T cells require two signals, IL-7 and a weak stimulation from the antigen receptor. We showed that this two signal requirement is based on IL-7 stimulation greatly amplifying weak antigen receptor signals. IL-7 strongly activated Lck which in turn greatly enhanced Zap70 activation by the antigen receptor. As part of the new Cancer and Inflammation Program, we initiated a new project. The goal is to create an inhibitor of bowel inflammation that would stop inflammatory bowel disease (and subsequent colon cancer) without systemically blocking host defense. To block IL-7 selectively in the bowel, we engineered a soluble form of the IL-7 receptor (IL-7-Fc) to be expressed by the food bacterium, Lactococcus lactis. This will be given orally to mice, aiming to block bowel inflammation and colon cancer.