Distinct Requirements for IL-7 in Development of TCRγδ Cells During Fetal and Adult Life

Abstract

TCRγδ-transgenic IL-7−/− mice were generated to determine whether T cells containing productively rearranged TCRγδ genes have additional requirements for IL-7 within the thymus or peripheral lymphoid tissues. Differences in developmental requirements for IL-7 by TCRγδ cells were noted and were linked to derivation from fetal- vs adult-type precursors in the thymus. Although TCRγδ cells are absent from IL-7−/− mice, TCRγδ cells were restored to the thymus and periphery by expression of TCRγδ transgenes. Endogenous TCRγ chains were expressed by IL-7+/− but not IL-7−/− TCRγδ-transgenic mice, providing direct support for findings that IL-7 is necessary for rearrangement and expression of TCRγ genes. The number of TCRγδ thymocytes was 10-fold reduced in TCRγδ-transgenic IL-7−/− embryos; however, adult TCRγδ-transgenic IL-7−/− or IL-7+/− mice had similar numbers of fetal thymus-derived TCRγδ cells in their skin. Thus, fetal TCRγδ cells required IL-7 for TCR rearrangement, but not for proliferation or survival in the periphery. In contrast, the numbers of TCRγδ cells in other tissues of TCRγδ-transgenic IL-7−/− mice were not completely restored. Moreover, coincident with the transition from the first to second wave of T cell precursors maturing in neonatal thymus, thymus cellularity of TCRγδ-transgenic IL-7−/− mice dropped significantly. These data indicated that in addition to TCRVγ gene rearrangement, TCRγδ cells differentiating from late fetal liver or adult bone marrow precursors have additional requirements for IL-7. BrdU incorporation studies indicated that although IL-7 was not required for TCRγδ cell proliferation, it was required to prolong the life span of mature TCRγδ cells.

γδ T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors

“…Likewise, ␥␦ T cell generation was rescued in IL-7 Ϫ/Ϫ mice upon grafting of an IL-7-expressing thymus (46). Additional BrdU labeling studies with ␥␦ TCR-transgenic IL-7 Ϫ/Ϫ mice suggested that IL-7, although not required for ␥␦ T cell survival, may increase the life span of proliferating cells, whereas other cytokines, such as IL-15, may be important for driving this proliferation (25), a prediction consistent with our present results. In regard to IL-15, studies indicated reductions in ␥␦ T cell subsets in IL-15 Ϫ/Ϫ , IL-15R␣ Ϫ/Ϫ , and IL-15R␤ Ϫ/Ϫ mice (26,47,48).…”

“…IL-7 signaling was shown to be absolutely required for the initiation of TCR␥ gene rearrangements (24). Consistent with this observation, ␥␦ T cells were absent in IL-7 Ϫ/Ϫ and IL-7R␣ Ϫ/Ϫ mice (22,23), but could be restored through introduction of a rearranged ␥␦ TCR transgene (25,45). Likewise, ␥␦ T cell generation was rescued in IL-7 Ϫ/Ϫ mice upon grafting of an IL-7-expressing thymus (46).…”

“…Both IL-7 and IL-15 are known to play significant roles in ␥␦ T cell development and/or tissue localization (22)(23)(24)(25)(26)(27)(28), but their effect on the overall ␥␦ T cell homeostasis has not been studied. Like conventional ␣␤ T cells, most ␥␦ T cells in LN and spleen expressed significant levels of the IL-7R␣ chain CD127 (Fig.…”

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…4B). Thus, consistent with previous reports (38,39), our data also suggested that IL-7Ra-mediated signaling was responsible for both the initial expansion and maintenance of gd T cells.…”

γδ T cell homeostasis is established in competition with αβ T cells and NK cells

“…Both IL-7 and IL-15 have been implicated in ␥␦ T cell biology and might play a role in ␥␦ T cell homeostasis. IL-7 is essential for rearrangement of the TCR␥ gene during ␥␦ T cell development (22,23) and may also increase ␥␦ T cell life span in the periphery (24). Although IL-15 is not required for ␥␦ T cell development in general, IL-15 Ϫ/Ϫ mice lack V␥5 ϩ epidermal ␥␦ T cells (25) and Thy1 Ϫ splenic and intestinal intraepithelial ␥␦ T cells (16,26).…”