dETCs and the Vγ6-positive Tγ:δ-17 cells develop exclusively from the early wave of hematopoietic stem cells derived from the fetal liver (see Fig. 8.22). Consequently, these two γ:δ T-cell subsets arise only for a brief period of time in the fetal thymus, and then never again. A second phase of γ:δ T-cell development is initiated in the fetal thymus just before birth. This phase persists at a low level in the adult thymus throughout life, and produces several subsets of cells, each with distinct effector functions and tissue homing properties. Like the dETCs and fetal Tγ:δ-17 cells, these later-developing γ:δ T cells can be generally classified by their usage of distinct Vγ–Vδ regions in their T-cell receptors (see Fig. 8.22), although the receptor sequences within each population are more diverse due to the presence of N-region nucleotides added by TdT.
One population of these later-developing γ:δ T cells is programmed to secrete IL-17 when activated; these represent a second subset of Tγ:δ-17 cells that express a different Vγ region than do the fetal Tγ:δ-17 cells. Specifically, these later-developing Tγ:δ-17 cells express T-cell receptors using the Vγ4 region. This Tγ:δ-17 subset is found in all lymphoid organs, as well as in the skin dermis and the intestinal epithelium, where the cells provide rapid inflammatory signals in response to bacterial and parasitic infections. In addition, γ:δ T cells using the Vγ7 region in their T-cell receptors also develop in this second phase. The Vγ7-positive γ:δ T cells home specifically to the intestinal epithelium. In that location, the cells are poised to respond to gut microbes that breach the epithelial barrier, and are important producers of antibacterial compounds as well as IFN-γ.
In contrast to the γ:δT-cell subsets that reside in barrier tissues such as the skin and intestinal epithelium, γ:δ T cells are also found in lymphoid organs. The majority of the lymphoid-resident γ:δ T cells arise during the late fetal–early neonatal period as well as thereafter, and represent a more diverse population expressing the Vγ1 region. Vγ1-positive T cells are composed of two major groups—an IFN-γplus IL-4-producing subset that homes to the liver as well as several lymphoid organs, and an IFN-γ-producing subset that homes to all lymphoid organs. The former population of cells, which can be identified by their expression of a unique TCRδ chain (Vδ6) that is paired to Vγ1, is remarkably similar to the α:β T-cell receptor-expressing subset of iNKT cells, and the cells are therefore often referred to as γ:δ NKT cells. Unlike the mucosal and epithelial resident γ:δ T-cell populations, whose importance in tissue homeostasis, repair, and innate defense against infections has been well established, the functions of γ:δ T cells within secondary lymphoid organs is still not well understood.
8-17 Successful synthesis of a rearranged β chain allows the production of a pre-T-cell receptor that triggers cell proliferation and blocks further β-chain gene rearrangement.