The mechanisms controlling growth and differentiation of hematopoietic cells is not fully understood. Many of the inputs regulating these processes are governed by growth factors binding to the cell surface and activating tyrosine kinases. These studies investigate the role of Src kinases in mediating the differentiation of an unusual lineage of lymphocyte, termed NKT cells. Specifically, we recently demonstrated that mutants in the Src-related tyrosine kinase, Fyn, are severely compromised in the formation of NKT cells, but conventional lymphocyte development proceeds normally. NKT cells comprise a unique class of lymphocyte with characteristics of both natural killer (NK) cells and T lymphocytes. NKT cells are capable of suppressing deviant immune responses, including graft versus host disease and autoimmunity, and tumor metastasis. NKT cells express a limited T cell receptor (TCR) repertoire, with most utilizing the TCR Valpha14Jalpha281 alpha chain. The restricted TCR use may have evolved because NKT cells recognize, and are selected by the nonpolymorphic class I-like molecule CD1d. The long-term goal of this project is to understand the role of tyrosine kinases in regulating the development and function of NKT cells. The studies outlined here will focus on two main areas. The first part will be devoted to identifying some of the molecular features of Fyn which allow it to transduce signals involved in NKT cell development. Transgenic mice expressing different forms of Fyn or retroviruses encoding Fyn variants will be used to infect mutant bone marrow cells, then determining whether the modified cells develop into NKT cells. The second area will focus on identifying the other constituents of the Fyn dependent pathway necessary for NKT cell development. It is hypothesized that this pathway is required for rearrangement of the TCR alpha locus, and that ectopic expression of the Valpha14Jalpha281 alpha chain will stimulate NKT cell development in the fyn mutants. In addition, we will test the hypothesis that Fyn facilitates signaling from the GM-CSF receptor to promote NKT cell development.
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