| For a great number of diseases, from Severe Combined Immune Deficiency to many leukemias, the most promising treatment is Hematopoietic Stem Cell Transplantation (HSCT). Despite being a treatment of choice for many years, it is still fraught with complications, including histoincompatibility, and often poor immune development.; The role of cytokines in the development of CD4+ T lymphocytes from Hematopoietic Stem Cells (HSC) is only beginning to be fully appreciated. The long-term repopulating subset of HSC undergoes a series of directed changes, in which it may become several different cell types. These decisions appear to depend on a number of factors, including proteins that bind to the cell surface, and the microenvironment in which it resides. My research focuses on two factors involved in the development and survival of naive T lymphocytes, Kit and Interleukin-7 (IL-7).; The IL-7 receptor (IL-7R) is expressed on the surface of naive T lymphocytes, and is known to contribute to their survival and proliferation. It is a heterodimer of the IL-7Ralpha subunit, and the common Gamma Chain (gamma c). Our research shows that it is necessary for the survival and homeostatic proliferation of naive T cells in vivo.; IL-7R is also expressed in early progenitor cells in the bone marrow, including Common Lymphoid Progenitors (CLP), where it shares expression with Kit. Our research demonstrates that both IL-7R and Kit signaling contribute non-redundantly to maintenance of CLP numbers in the bone marrow. Kit also affects the number of HSC in the bone marrow. Unexpectedly, our research has discovered that mice which lack the gammac have a markedly increased number of HSC. This could have important consequences for X-linked SCID, in which humans lack the same receptor.; Finally, our data shows that IL-7R signaling results in changes in the transcription of hundreds of genes. Using microarrays, we are able to catalog these changes in primary naive T lymphocytes and compare them to similarly treated immature thymocytes. |
