A master gene that underpins the development of specific blood cell lineages has been identified by a research team led by Hiroshi Kawamoto at the RIKEN Research Center for Allergy and Immunology in Yokohama. The team has published its findings in the journal Science1.
Precursor cells in the immune system, known as hematopoietic progenitor cells, can give rise to multiple immune cell types. Kawamoto and his team cultured multipotent progenitor cells from mice that could become T cells that shape the immune response, B cells that generate antibodies, or myeloid cells that can engulf pathogens. Their special culture system could stimulate the Notch signaling pathway, which is required for progenitor cell renewal, and included immune system regulators such as interleukin-7 (IL-7).
The researchers found they could induce the immune progenitor cells to lose their ability to become B cells under these conditions. However, this halted development of the cells past this stage, as the progenitors were unable to cease proliferating and mature into either T cells or myeloid cells.
Kawamoto and colleagues then observed that removing IL-7 from the cell culture medium was sufficient to drive the progenitors to mature into T cells. They found that withdrawing IL-7 induced the expression of the transcription factor Bcl11b, which is known to be expressed in T cells. Interestingly, even when IL-7 was present in the cell culture medium, they could push immune progenitor cells into becoming T cells by forcing Bcl11b to be expressed in the cells. This suggested to the researchers that this transcription factor drives this step in the commitment of these immune progenitor cells to the T cell lineage.
The team also showed that progenitor cells lacking the Bcl11b gene were unable to mature into T cells, and could continue to proliferate (Fig. 1). This is consistent with previous findings by other research teams that disruption of the function of Bcl11b is linked to leukemia and lymphoma, which may be caused by the inability of the progenitor cells to mature properly into T cells, and to instead continue to proliferate. Kawamoto and his colleagues think that Bcl11b may drive progenitor cells to take on the T cell fate by suppressing the genes that characterize the myeloid cell lineage.
“Our findings may facilitate the study of the molecular mechanisms of T cell lineage commitment by elucidating the exact timing for this commitment,” explains Kawamoto, “and by identifying a master gene for the establishment of T cell lineage.”
The corresponding author for this highlight is based at the Laboratory for Lymphocyte Development, RIKEN Research Center for Allergy and Immunology
1. Ikawa, T., Hirose, S., Masuda, K., Kakugawa, K., Satoh, R., Shibano-Satoh, A., Kominami, R., Katsura, Y. & Kawamoto, H. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010).
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