Development of Interleukin-17-Producing γδ T Cells Is Restricted to a Functional Embryonic Wave

Abstract

γδ T cells are an important innate source of interleukin-17 (IL-17). In contrast to T helper 17 (Th17) cell differentiation, which occurs in the periphery, IL-17-producing γδ T cells (γδT17 cells) are probably committed during thymic development. To study when γδT17 cells arise during ontogeny, we used TcrdH2BeGFP reporter mice to monitor T cell receptor (TCR) rearrangement and IL-17 production in the embryonic thymus. We observed that several populations such as innate lymphoid cells and early T cell precursors were able to produce IL-17 prior to (and thus independent of) TCR recombination. γδT17 cells were absent after transplantation of IL-17-sufficient bone marrow into mice lacking both Il17a and Il17f. Also, γδT17 cells were not generated after genetic restoration of defective Rag1 function in adult mice. Together, these data suggested that these cells developed exclusively before birth and subsequently persisted in adult mice as self-renewing, long-lived cells.

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…These cells circulate in blood and reside in the dermis, lung, liver and secondary lymphoid organs. In according to Haas et al 50. ‘natural’ γδ 17 cells (V γ 6 + and part of V γ 4 + ) developed before birth acquire interleukin‐17 ( IL ‐17) ‐producing ability in thymus and produce IL ‐17 stimulated by IL ‐1 β and IL ‐23 in the periphery.…”

“…Early T‐cell precursors can produce IL‐17 before TCR recombination50 and Sox4 and Sox13 are expressed before activation with TCR signalling 42. Antigen‐naive γδ T cells in the thymus differentiate into IL‐17 producers, whereas antigen‐experienced cells make IFN‐ γ 28.…”

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

“…3A, 3B). Vg4 + gd T cells are a major subset of IL-17 1 gd T cells (9) [Heilig and Tonegawa's (35) nomenclature for TCRg genes was used]. Among Vg4 + gd T cells, IL-17 + cells were selectively decreased in the absence of RBP-Jk (Fig.…”

“…Unlike conventional ab T cells, which are exported from the thymus as naive cells and acquire effector functions upon Ag encounter in the periphery, some murine gd T cells, so-called naturally occurring gd T cells, harbor innate functions to produce inflammatory cytokines, such as IFN-g and IL-17, within thymus. They are disproportionately distributed and persist in mucosal epithelia, such as skin, intestine, uterus, and lung, as tissue-associated, long-lived self-renewing cells that are important players in mucosal immunity in infections, wound healing, autoimmune disorders, and tumors (7)(8)(9)(10)(11). Interaction between Notch1 and Dll4 is essential for gd T cell development from T cell precursors, and Notch1 expression is maintained on gd T cells (12)(13)(14).…”

Diversity of γδ T-cell antigens

“…Nevertheless, specific evidence concerned with IL-17 producing cd T cells suggests that, at least in this case, the correlation between cd TCR expression and function is merely coincidental-waves of cd T cells expressing certain TCRs coincide with a thymic environment that temporarily favors TH17 differentiation. 11 Although there is still less experimental evidence, segregation of TCR-defined cd T-cell subsets (both spacial and functional) has also been found in other species and might well be a universal feature of these cells. With regard to Ag specificity, one immediate consequence of this is a partial repertoire restriction, and the association of certain repertoires with certain functions.…”