For the first time human embryonic stem cells have been coaxed into becoming T-cells, suggesting new ways to fight immune disorders including AIDS and the 鈥渂ubble boy鈥� disease, X-SCID.
Embryonic stem cells (ESCs) are an attractive source of human T-cells for research and therapy because ESCs can be genetically manipulated with relative ease and can be grown in large quantities.
T-cells are crucial to the working of the immune system. If these cells are destroyed or absent 鈥� as occurs during HIV infection and X-SCID, respectively 鈥� the body cannot fight off infections. But despite their importance, much about human T-cell function is unknown because the cells are difficult to analyse with standard tools of genetic engineering.
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鈥淚ntroducing new genes is inefficient in T-cells and can activate the cells in inappropriate ways,鈥� says Jerome Zack at the David Geffen School of Medicine at the University of California, Los Angeles, US.
Three-step process
Instead, Zack鈥檚 team genetically-engineered ESCs and then pushed them to become T-cells in a three-step process. First the cells were given a gene for a green fluorescent protein using a genetically-engineered virus. Next, the cells were grown on mouse bone marrow cells. Finally, they were injected into a small piece of human thymus which had been implanted in a mouse with a deficient immune system.
The bone marrow and thymus are known to provide chemical factors necessary for normal T-cell development. In the end, as many as 24% of the T-cells in the implanted thymus proved to have derived from the green fluorescent ESCs 鈥� the rest were produced by the thymus from progenitor cells supplied by a small piece of human liver that was part of the transplant.
The technique opens many possibilities. For genetic diseases, like X-SCID 鈥� a severe immunodeficiency, often fatal in the early years of life 鈥� ESCs derived from the patient could be given a functional version of the defective T-cell gene. For HIV, ESCs could be engineered to inactivate the gene for CCR5, a surface molecule that the virus needs to successfully attack T-cells.
Key player
However, the future of all ESC-based therapy remains uncertain as it is not yet known if ESCs can be immunologically matched to a patient by therapeutic cloning or by selecting a match from a large bank of different ESCs (see After the hype: What Dolly the sheep really did for us).
鈥淭his is certainly not ready for prime time in the clinic,鈥� Zack says. Robert Lanza of Advanced Cell Technology based in Alameda, California, US, says the work 鈥渓ays the foundation for the potential future treatment of various blood disorders鈥�.
For now, Zack鈥檚 team is eager to exploit the new technique to better understand the T-cell, a key player in the human immune system.
Amy Wagers, a stem cell biologist at Harvard Medical School in Boston, Massachusetts, US, says that alone would be an important advance. 鈥淚n the near term, this gives you a much more versatile model system to study human T-cells.鈥�
Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.0604244103)
