B.J. Fowlkes, Ph.D.Building 4, Room 1114 Memorial DriveBethesda, MD 20892-0420Phone: 301-496-5530Fax: email@example.com
T lymphocytes have evolved sophisticated mechanisms for generating a diverse repertoire of antigen receptors (TCR) that enable them to respond to a vast array of foreign organisms. During development, thymocytes undergo a testing process (positive and negative selection) to ensure that cells expressing useless or self-reactive receptors do not mature. These positive and negative selection processes both involve TCR-MHC engagement, but different aspects of these interactions must trigger cells to live or die.
Our studies of TCR-transgenic and gene-targeted mutant mice indicate that quantitative differences in MHC recognition determine whether a thymocyte will undergo positive or negative selection, or fail to be selected at all. Moreover, the quantity of signal within the acceptable range for positive selection also influences whether the developing T-cell will become a CD4 helper or CD8 cytotoxic T-cell. In other experiments in which the expression of MHC and/or other self-antigens was manipulated, we found that the nature and distribution of thymic antigens could affect the functional competence of emerging, mature T-cells.
Much of our work is aimed at elucidating mechanisms controlling cell fate decisions. We have characterized thymocytes for TCR usage, phenotype, and functional competence, and we have investigated maturational state, precursor/product, and lineage relationships. There are two major lineage decisions for developing T-cells: 1) T-cell precursors mature in the g/d or α/β lineage, and 2) those that develop in the α/β pathway must choose a CD4 or CD8 T-cell fate. Because we and others have demonstrated that the TCR plays a major role in many cell fate decisions, our present efforts are focused on how TCR signals are integrated with other developmental cues to regulate death vs. survival, proliferation, maturation, and lineage commitment.
Roche Basic Science Award, NIH Merit Award, AAI Outstanding Investigator Award.
Chris Fleischacker, Francesca Macchiarini, Errin Matechak, Hillary Noll.
(View current list in PubMed.)
Ramsdell F, Fowlkes BJ. Maintenance of in vivo tolerance by persistence of antigen. Science. 1992. 257: 1130-1134.
Robey EA, Ramsdell F, Kioussis D, Sha W, Loh D, Axel R, Fowlkes BJ. The level of CD8 expression can determine the outcome of thymic selection. 1992. Cell. 69: 1089-1096.
Schweighoffer E, Fowlkes BJ. Positive selection is not required for thymic differentiation of transgenic g/d cells. J Exp Med. 1996. 183: 2032.
Matechak E, Killeen N, Hedrick SM, Fowlkes BJ. MHC class-II specific T-cells can develop in the CD8 lineage when CD4 is absent. Immunity. 1996. 4: 337-347.
Robey EA, Fowlkes BJ. Selective events in T-cell development. Annu Rev Immunol. 1994. 12: 675-705.
Robey EA, Fowlkes BJ. The a/b versus g/d T-cell lineage choice. Curr Opinion Immunol. 1998. 10: 181.
Special Interest Groups: Immunology.
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Last Updated March 27, 2013