The earliest thymic progenitors for T cells possess myeloid lineage potential

Abstract

There exists controversy over the nature of haematopoietic progenitors of T cells. Most T cells develop in the thymus, but the lineage potential of thymus-colonizing progenitors is unknown. One approach to resolving this question is to determine the lineage potentials of the earliest thymic progenitors (ETPs). Previous work has shown that ETPs possess T and natural killer lymphoid potentials, and rare subsets of ETPs also possess B lymphoid potential, suggesting an origin from lymphoid-restricted progenitor cells. However, whether ETPs also possess myeloid potential is unknown. Here we show that nearly all ETPs in adult mice possess both T and myeloid potential in clonal assays. The existence of progenitors possessing T and myeloid potential within the thymus is incompatible with the current dominant model of haematopoiesis, in which T cells are proposed to arise from lymphoid-. Our results indicate that alternative models for lineage commitment during haematopoiesis must be considered.

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].…”

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

“…It is generally believed that the so-called thymic seeding precursor (TSP) still has the capability of generating B cells, NK cells, DCs and other myeloid cells [2,5,6,10,11]. Upon receiving the Notch signal, the differentiation potential towards the B-cell lineage of the TSP is rapidly lost [2,10,11], whereas other lineage options are still maintained [2,5,6,10,11]. However, a recent study using an IL-7Ra reporter mouse indicated that the non-T-cell lineage differentiation of these progenitors is not, or only very rarely, occurring under physiologic conditions [12,13].…”

“…In transplantation settings, it has been shown that different progenitors can home to the thymus and generate T cells [1][2][3][4][5][6][7][8][9]. However, under physiological conditions the role of each of these progenitors is still unclear.…”

“…DN1 cells express high cell surface levels of CD44 and CD117, and are negative for CD25, whereas their DN2 progeny express all three markers [14][15][16]. In vitro, DN1 and DN2 cells still possess the capacity to differentiate into NK cells, DCs and other myeloid cells [5,6,11,17] suggesting that they are not yet restricted to the T-cell lineage. T-cell commitment is achieved at the DN3 stage.…”

Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases

“…They suggest a community with T-ALL, 26,27,47 which could be related to the existence of the recently identified common macrophage-T progenitor. 48,49 Both MYST3-linked AMLs and T-ALLs could originate from this common progenitor; variation in the dosage of regulatory factors could further induce leukemia in either the T-lymphoid or myelomonocytic lineage. The regulation of early myelomonocytic differentiation, which is controled by a complex network of factors, 50 is affected at several levels in t(8;16) leukemia including the formation of chimeric HATs, amplification of MYB and overexpression of HOXA genes.…”