Title

The roles of stem cell factor and interleukin-7 in development of TCRgammadelta cells

Date of Completion

January 1999

Keywords

Biology, Cell|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Interleukin 7 (IL-7) is absolutely required for development of TCRγδ cells. IL-7 deficient (IL-7–/–) mice have reduced numbers of B and TCRαδ cells, but completely lack mature TCRγδ cells. To date, the precise role of IL-7 in TCRγδ development has not been pinpointed. We have used neonatal thymectomy (nTx) and thymus grafting, tissue-specific iFABP-IL7 transgenic IL-7–/– mice, or G8 TCRγδ-transgenic IL-7–/– mice to identify IL-7 dependent stages of TCRγδ cell development. The data presented show that IL-7 first acted on T cell precursors to stimulate TCRγ gene rearrangement. Expression of a fully rearranged TCRγδ transgene restored TCRγδ cells to IL-7 –/– mice, and endogenous TCRγ chains were expressed by TCRγδ cells in G8 IL-7+/– mice, but not G8 IL-7–/– mice. IL-7 directed TCRγ gene rearrangement in two different anatomic locations: in the thymus for thymus-derived TCRγδ cells, or in the intestinal epithelium for extrathymic TCRγδ intraepithelial lymphocytes (IEL). TCRγδ cells developed in IL-7 + thymi that had been grafted to nTx IL-7–/– mice. TCRγδ IEL also developed in IL-7–/– mice in which IL-7 expression was restored specifically to the intestinal epithelium. TCRγδ+ thymocytes derived from early fetal liver precursors did not require additional IL-7. In contrast, the survival of TCRγδ+ thymocytes derived from late fetal liver or adult bone marrow was IL-7 dependent. Neither fetal liver- nor bone marrow-derived mature TCRγδ cells required extrathymic IL-7 in order to survive. Instead, the maintenance and proliferation of TCRγδ IEL was dependent upon another cytokine, stem cell factor (SCF). Mice with a reduced function mutation in the SCF receptor c-Kit (W/ WV), had reduced numbers of TCRγδ IEL, because in the absence of optimal SCF/c-Kit interactions TCRγδ cells proliferated less. With regard to the role of IL-7 in the development of TCRγδ cells, these data illustrated that IL-7 influenced immature TCRγδ cells at multiple stages, and that the developmental requirements of TCRγδ cells arising at different times during ontogeny differed in their dependence upon IL-7. These data also provided the first unequivocal evidence that extrathymic TCRγδ IEL development occurred in situ, within the intestinal epithelium. ^