The goal of this work will be to determine the limits of the efficiency and total number of T cells that can be produced in the thymus, and to identify whether particular cytokines, stromal cells, or precursor cells determine the limits of this process.
Specific Aims : 1) Measure the number of T cells that are produced in mice whose T cell receptor genes are derived from a mouse cloned from a T cell. Measure this number in respect to the number of thymic precursors, and establish a maximum productivity of the thymus for this T cell. 2) Test whether the efficiency of generation of this mature T cell from progenitors increases upon the dilution of precursors containing the proper TCR. Generate a number of maximum efficiency based on precursor dilution using bone marrow and blastocyst chimeras and parabiosis. 3) Test the hypothesis that factors such as selecting peptide, stromal cells or other T cells, cytokines IL-7 or c-kit can modulate the efficiency of generation and/or total ouput of T cells from the thymus. The findings of this study will be particularly relevant in for designing treatments that enhance recovery of T cell functions after bone marrow transplant, chemotherapy, or during recovery from diseases that deplete T cells. In addition, it will be directly relevant to therapies that would involve skewing of T cell development to favor T cells with desired specificities.
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| Inlay, Matthew A; Bhattacharya, Deepta; Sahoo, Debashis et al. (2009) Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development. Genes Dev 23:2376-81 |
| Karsunky, Holger; Inlay, Matthew A; Serwold, Thomas et al. (2008) Flk2+ common lymphoid progenitors possess equivalent differentiation potential for the B and T lineages. Blood 111:5562-70 |
| Serwold, Thomas; Hochedlinger, Konrad; Inlay, Matthew A et al. (2007) Early TCR expression and aberrant T cell development in mice with endogenous prerearranged T cell receptor genes. J Immunol 179:928-38 |
| Forsberg, E Camilla; Serwold, Thomas; Kogan, Scott et al. (2006) New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126:415-26 |
