Our ultimate objectives are to define the progenitor cells which generate the major classes of functional T-lymphocytes, to trace the pathways along which these progenitor cells differentiate and to define the factors which determine the choice of a specific pathway and which regulate cell proliferation and differentiation. Mature thymus-derived lymphocytes descend from progenitor cells. One such progenitor is an intrathymic progenitor which is defined by its ability to proliferate within the thymus of an irradiated animal and to transiently repopulate it. Murine thymocyte populations which are 50-100 fold enriched for the thymus-homing progenitor cell can be isolated by cytotoxic ablation of most mature thymocytes.
One aim of this project is to characterize the thymocyte progenitors within this population. A combination of flow cytometry, immunodepletion, and in vivo and in vitro functional analysis will be used to study progenitor cell heterogeneity and to trace the events occurring during thymus repopulation and migration of thymus emigrants to the periphery. There is, however, no satisfactory in vitro system permitting the growth of thymocyte progenitors in pure culture and in large quantity. The use of temperature-sensitive retroviruses to establish progenitor cell lines which can be induced to differentiate to recognizable progeny will be evaluated using organ cultures of fetal thymocytes and a temperature-sensitive mutant of Abelson murine leukemia virus. Mature thymus-derived lymphocytes are the descendants of one or more generative pools within the thymus. The transferrin receptor is a marker for cells within this generative pool and is a tumor- associated marker for thymus lymphomas. Anti-transferrin receptor antibody can be used to inhibit the growth of thymus lymphomas in vitro.
A final aim of this project is to study the mechanism by which antitransferrin receptor antibody inhibits cell growth by studying transferrin receptor turnover and synthesis in thymus lymphomas grown in anti-transferrin receptor antibody and by studying the biochemical and genetic basis of mutants resistant to the growth inhibitory effects of anti-transferrin receptor antibody.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Salk Institute for Biological Studies
La Jolla
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Lesley, J; He, Q; Miyake, K et al. (1992) Requirements for hyaluronic acid binding by CD44: a role for the cytoplasmic domain and activation by antibody. J Exp Med 175:257-66
Hyman, R; Lesley, J; Schulte, R (1991) Somatic cell mutants distinguish CD44 expression and hyaluronic acid binding. Immunogenetics 33:392-5
Lesley, J; Trotter, J; Schulte, R et al. (1990) Phenotypic analysis of the early events during repopulation of the thymus by the bone marrow prothymocyte. Cell Immunol 128:63-78
Reynolds, P J; Lesley, J; Trotter, J et al. (1990) Changes in the relative abundance of type I and type II lck mRNA transcripts suggest differential promoter usage during T-cell development. Mol Cell Biol 10:4266-70
Lesley, J; Schulte, R; Hyman, R (1990) Binding of hyaluronic acid to lymphoid cell lines is inhibited by monoclonal antibodies against Pgp-1. Exp Cell Res 187:224-33
Lesley, J; Schulte, R; Woods, J (1989) Modulation of transferrin receptor expression and function by anti-transferrin receptor antibodies and antibody fragments. Exp Cell Res 182:215-33
Heyman, R A; Borrelli, E; Lesley, J et al. (1989) Thymidine kinase obliteration: creation of transgenic mice with controlled immune deficiency. Proc Natl Acad Sci U S A 86:2698-702
Lesley, J; Schulte, R; Hyman, R (1988) Kinetics of thymus repopulation by intrathymic progenitors after intravenous injection: evidence for successive repopulation by an IL-2R+, Pgp-1- and by an IL-2R-, Pgp-1+ progenitor. Cell Immunol 117:378-88
Lesley, J; Schulte, R; Trotter, J et al. (1988) Qualitative and quantitative heterogeneity in Pgp-1 expression among murine thymocytes. Cell Immunol 112:40-54
Trowbridge, I S; Lesley, J F; Domingo, D et al. (1987) Monoclonal antibodies to transferrin receptor and assay of their biological effects. Methods Enzymol 147:265-79

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