Random Walk
T Cells Make a Commitment
When does a cell choose its particular identity? That’s one of the big questions in biology. We now know the answer, at least for a branch of the immune system called T cells.
The activation of a gene called Bcl11b is a “clean, nearly perfect indicator of when cells have decided to go on the T-cell pathway,” says Ellen Rothenberg , the Ruddock Professor of Biology at Caltech.
The Bcl11b gene acts to shut off other genes in the stem cells from which T cells are born, allowing the stem cells to pick one of the many developmental paths open to them.
“Stem cells and their multipotent descendents follow one set of growth rules, and T cells another,” says Rothenberg, “so if T-cell precursors don’t give up certain stem-cell functions, bad things happen.”
The conversion from T-cell precursors to actual T cells takes place in the thymus, a specialized organ located near the heart. “When the future T cells move into the thymus,” Rothenberg explains, “they are expressing a variety of genes that give them the option to become other cells,” such as mast cells (which are involved in allergic reactions), killer cells (which kill cells infected by viruses), and antigen-presenting cells (which help T cells recognize targeted foreign cells).
As the T cells enter the thymus, the organ sends molecular signals to the cells, directing them down the T-cell pathway. At this point, the Bcl11b gene gets turned on, blocking other pathways. This is critical.
“For cells that never divide again, maintaining identity is trivial. What they are at that moment is what they are forever,” Rothenberg says. But T cells keep dividing as they migrate around the body and interact with other types of cells.
The Bcl11b protein “is like a switch that allows the cells to shut off stem-cell genes and other regulatory genes,” Rothenberg says. “It keeps them clean—and may be necessary to ‘guard’ the T cell from becoming some other type of cell.”
Although it is thought that many genes are involved in the process of creating and maintaining T cells, “Bcl11b is the only regulatory gene in the whole genome to be turned on at this stage,” she adds, “and it is probably always active in all T cells. It is the most T-cell specific of all of the regulatory factors discovered so far.” Among blood cells, this gene is only expressed in T cells, she says. “The gene is used in other cells in completely different types of tissue, such as brain and skin and mammary tissue, but that’s how the body works. There’s no confusion, because something like brain tissue and mammary tissue will never be a T cell.”
When Bcl11b is not present—as in mice genetically altered to lack the gene—T cells “don’t turn out right,” Rothenberg says. Indeed, T cells in some individuals with T-cell leukemia have been found to have lost the gene. “It may make them more susceptible to the effects of radiation, because the cells don’t know when to stop growing,” she says. “We think that the loss of one of the two copies of the gene is enough to prevent cells from growing appropriately.”
The discovery is described in “An Early T Cell Lineage Commitment Checkpoint Dependent on the Transcription Factor Bcl11b,” a paper in the July 2 issue of Science—one of three papers on the Bcl11b gene. The paper was coauthored by Rothenberg, Caltech postdoc Long Li, and Mark Leid of Oregon State University. The work was supported by the California Institute for Regenerative Medicine, the National Institutes of Health, the Caltech–City of Hope Biomedical Research Initiative, the Louis A. Garfinkle Memorial Laboratory Fund, and the Al Sherman Foundation. —KS
