Lineage infidelity in myeloid cells with TCR gene rearrangement: A latent developmental potential of proT cells revealed by ectopic cytokine receptor signaling

Abstract

The most immature lymphoid-committed progenitors in both the bone marrow (common lymphoid progenitor) and thymus (proT1) maintain a latent granulocyte͞macrophage (G͞M) differentiation potential that can be initiated by signals emanating from exogenously expressed IL-2 receptors. In this study, we investigate at which developmental stage thymocytes lose this G͞M differentiation potential. We demonstrate that the next maturational stage after proT1 cells (proT2), but not preT (TN3) cells, can convert cell fate from lymphoid to myeloid in response to ectopic IL-2 receptor signaling in human IL-2R␤ transgenic mice. It is significant that approximately 10% of clonogenic G͞M colonies derived from proT cells of IL-2R␤ transgenic mice have DJ rearrangement specifically at the D␤1 but not D␤2 segment in the TCR␤ locus. No TCR gene rearrangement is observed in G͞M cells from nontransgenic mice, suggesting that the G͞M cells we observe in this system were truly lymphoid-committed before stimulation with IL-2. In addition, D␤1 and D␤2 DJ rearrangement of the TCR␤ gene may be differentially regulated and thus serve as markers for distinct proT cell maturational stages.

E2a/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells

“…Percentiles of EGFP þ cells are indicated; data are representative of two independent experiments. pro-T4), which could be unveiled by stimulating ectopically expressed IL-2 or GM-CSF receptors (Kondo et al, 2000;King et al, 2002;Iwasaki-Arai et al, 2003). Moreover, the macrophage differentiation of purified mouse embryonic thymocytes could be obtained in vitro with a specific combination of cytokines, provided that M-CSF was present (Lee et al, 2001), which suggested that M-CSF-R could be naturally expressed in early T progenitors.…”

“…Moreover, the macrophage differentiation of purified mouse embryonic thymocytes could be obtained in vitro with a specific combination of cytokines, provided that M-CSF was present (Lee et al, 2001), which suggested that M-CSF-R could be naturally expressed in early T progenitors. It has been proposed that one of the earliest event in lymphoid lineage commitment is downregulation of cytokine receptors whose normal function is to drive and support myeloid lineage differentiation (Kondo et al, 2000;King et al, 2002;Iwasaki-Arai et al, 2003). As pro-T cells are developing into lymphocytes, they gradually lose all differentiating potential into the myeloid lineage (King et al, 2002).…”

“…It has been proposed that one of the earliest event in lymphoid lineage commitment is downregulation of cytokine receptors whose normal function is to drive and support myeloid lineage differentiation (Kondo et al, 2000;King et al, 2002;Iwasaki-Arai et al, 2003). As pro-T cells are developing into lymphocytes, they gradually lose all differentiating potential into the myeloid lineage (King et al, 2002). Accordingly, when the murine M-CSF-R was retrovirally transferred in the IL-2-dependent T-cell line CTLL-2, cells proliferated in response to M-CSF without differentiating to macrophages (our unpublished data).…”

“…Indeed, low levels of c-fms transcripts have been detected in pluripotent hematopoietic cells, but cell surface expression of the receptor is detectable only later in the monocytic lineage (Tagoh et al, 2002;Follows et al, 2005). M-CSF-R transcript expression has been also detected within the thymus in the earliest sub-population that exhibits both T-lymphoid and macrophage, but no B-lymphoid potentials (Balciunaite et al, 2005), and it has been proposed that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid differentiation, including the M-CSF-R (Kondo et al, 2000;King et al, 2002). Altogether, data suggest that M-CSF-R may be implicated in early steps of hematopoiesis, notably in mechanisms determining cell fate toward either myeloid or T-lymphoid development.…”

Antagonistic effect of CCAAT enhancer-binding protein-α and Pax5 in myeloid or lymphoid lineage choice in common lymphoid progenitors

“…Stimulation through ectopic cytokine receptors, such as IL-2 and GM-CSF receptors, uncovers a latent myeloid differentiation potential in CLPs and proT (DN1 and DN2) cells (9)(10)(11). Although using an artificial system, IL-2-induced lineage conversion in CLPs is a clear evidence demonstrating that cytokines can have instructive actions in determining lymphoid vs. myeloid lineage outcome (12).…”