Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Abstract

Key Points• Granulocytes in the adult mouse thymus share a common origin with T cells, because they derive from ETPs.• The finding that ETPs generate myeloid cells in vivo indicates that precursors settling the thymus include myelolymphoid progenitors. IntroductionSince the identification of early T-lineage precursors (ETPs), 1 much work has characterized the developmental potentials possessed by this population. [2][3][4][5][6][7][8][9][10][11][12][13] In addition to robust T-cell developmental potential, ETPs have been shown to possess B cell, dendritic cell (DC), and natural killer (NK) cell potential and a degree of myeloid potential. As ETPs progress along the T-cell developmental pathway, they gradually lose non-T-cell potentials and generate CD4/ CD8-double negative 2 (DN2) progenitors and, finally, DN3 cells that are committed to the T-cell lineage. Single-cell assays using a stromal cell culture system have shown that the majority of individual ETPs can give rise to both T cells and myeloid cells, including granulocytes and macrophages. 10,11 However, less is known about the extent to which ETPs realize this myeloid potential and other non-T-cell lineage potentials in vivo. We reported previously that approximately half of ETPs and a similar fraction of thymic granulocytes were labeled in H2-VEX V(D)J recombination reporter mice. 10 These data are consistent with the notion that thymic granulocytes share a common origin with T cells. Since then, another study examining thymic myeloid cells using an IL-7 receptor (IL-7R)/Cre lineage tracing approach yielded discordant results. 12 Therefore, further examination was needed to determine whether ETPs can produce granulocytes in vivo and whether ETPs are the major precursors of thymic granulocytes. An understanding of whether ETPs generate both myeloid and T-cell progeny in vivo will contribute to a more complete model of hematopoietic development.In the present study, we examined thymic granulocyte development in experimental contexts in which ETPs are nearly absent. We reasoned that non-T-lineage cells in the thymus that are unperturbed in the absence of ETPs in mixed-BM chimeras must not predominantly derive from ETPs. Previous studies used a similar approach to investigate whether non-T-lineage cells in the thymus originate from T-cell progenitors; however, these studies did not examine thymic granulocytes. 14,15 Studies using models that exclusively block intrathymic ETP development (eg, by ablating Notch signaling) may fail to detect a common origin with T-cell progenitors because progenitors continue to settle the thymus and may still generate non-T-lineage cells even when ETP development is abrogated. To address this concern, we chose to study the development of non-T-lineage cells in the thymus by eliminating T-cell progenitors before thymic entry. Specifically, we examined mixed chimeras using CCR7/CCR9 double-deficient donor BM in which T-cell progenitors display defective thymic settling and thus generate almost no ETPs. In addition, we examined ...

Transcriptional Regulation of Innate and Adaptive Lymphocyte Lineages

“…Specifically, a myeloid-lymphoid progenitor intermediate stage between MPPs and CLPs has been identified (15)(16)(17); these cells, termed lymphoid-primed multipotent progenitors (LMPPs), can express IL-7Rα, although at levels below those seen in CLPs (12,(18)(19)(20). In vivo, some T cells appear to derive directly from myeloid-lymphoid-restricted LMPPs (21)(22)(23) (Figure 2). Further, the originally identified CLP population has been shown to be Overview of T cell and innate lymphoid cell development.…”

“…ETPs retain the potential to develop into non-T cell lymphoid cells (B cells and NK cells/ILCs), DCs, and, to a degree, myeloid cells (22,26,46,93,99,(123)(124)(125)(126)(127)(128). Although it is clear that ETPs retain several alternative potentials, less is known about whether they adopt non-T cell fates in vivo.…”

“…In addition, ETPs access some myeloid fates in the thymus in vivo. Specifically, thymic granulocytes derive almost exclusively from ETPs in vivo (22). Accordingly, thymic granulocytes, unlike peripheral conventional granulocytes, are labeled by a history of Rag1 expression and rely on similar cytokine/chemokine receptor and transcription factors as early T cell progenitors for their development (IL-7Rα, γc, CCR7, CCR9, and Hes1) (22).…”

“…Specifically, thymic granulocytes derive almost exclusively from ETPs in vivo (22). Accordingly, thymic granulocytes, unlike peripheral conventional granulocytes, are labeled by a history of Rag1 expression and rely on similar cytokine/chemokine receptor and transcription factors as early T cell progenitors for their development (IL-7Rα, γc, CCR7, CCR9, and Hes1) (22). T cell progenitors may contribute to macrophages and cDCs in the thymus; however, there are likely to be more efficient sources for these lineages (22,125,132,138).…”

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

“…It was initially thought that thymic settling progenitors lost myeloid potential before acquiring either T or B potential but a few recent studies showed that some progenitors within the thymus had lost B potential while retaining myeloid potential [49][50][51]. These data raised some controversy as it was questioned as to whether this myeloid differentiation occurs under physiological conditions within the thymus itself [52,53] but it was very recently reported that ETPs give rise to the majority of thymic granulocytes [54]. Thus, it appears that the progenitors that normally seed the thymus, while incapable of supporting long-term T-cell differentiation, can give rise to multiple blood cell lineages.…”