An international team of academic and commercial researchers has discovered new information about how our immune system makes T cells that could help make purified T cells without the need for “feeder” cells: such an advance would be a big step forward for transplantation and regenerative medicine, as well as opening up new avenues for research and applications in drug and toxicity testing in industry.

The researchers have written about their findings in a paper published online on 18 January in the Journal of Experimental Medicine. Dr Martin Turner a Group Leader and Head of the Lymphocyte Signalling and Development Laboratory at the Babraham Institute in Cambridge, UK, led the team, which included researchers from the UK, Japan, GlaxoSmithKline USA and a Da Vinci exchange student from Italy.

The Babraham is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC), which funded the study with the Medical Research Council (MRC).

T cells or T lymphocytes are white blood cells that play a central role in our immune system’s ability to recognize and fight infection. The more we understand about how they develop, acquire specialized functions, and how things can go wrong and lead to lymphomas (cancers that begin in lymphocytes), the better our chances of developing new and effective treatments. As Turner told the press:

“A goal of research in the field of regenerative medicine is T cell reconstitution for therapeutic purposes.”

He and his team have discovered for the first time how immature T cells can be grown without the need for “feeder” cells. Feeder cells can’t be separated easily from the required T cells; finding a new way to make T cells without using feeder cells is thus a significant step in regenerative medicine.

Lead author Dr Michelle Janas, also of the Babraham Institute, said:

“One of the challenges for the scientific community is to reproduce the process of T cell development in the laboratory.”

“This technology could enable the production of T cells for clinical applications such as their transplantation into immuno-compromised individuals,” she added.

T cells develop in the thymus (an organ that sits in the chest cavity just behind the sternum) and originate from progenitor stem cells that are made in and travel from the bone marrow.

The process of T cell development is complicated and involves many different types of biochemical signals and growth factors, each binding to the T cell and sending signals inside the cell that cause genetic changes that mature the T cell so it can detect and trigger attacks on foreign bodies like viruses, bacteria and fungi.

Our thymus is very active making T cells in early life and childhood, but starts to shrink when puberty sets in, and we make fewer and fewer T cells as we get older. For most healthy people this is not a problem, but when we have to undergo challenging procedures like chemotherapy or radiotherapy, or if we contract serious infections like HIV/AIDS, our bodies find it extremely difficult to replace T cells and we end up with very low reservoirs of lymphocytes, a condition known as T cell lymphopenia.

Impaired thymic activity results not only in low levels of T cells but also loss of diversity, further hampering our ability to fight infection, and leaving us more vulnerable to opportunistic infections.

Even after a bone marrow transplant, it can take at least two years for T cell numbers to go back to normal.

Thus any discovery that helps make T cells as fast as possible, and overcomes some of the many hurdles faced in the use of T cells in tranplantations and regenerative medicine, is good news. It appears that the discovery at the Babraham may make it possible to produce pure tailor-made T cells for transplantation.

Janas said:

“The generation of T cells in culture is currently possible, but requires supporting feeder cells; these mimic the thymus environment but have the disadvantage of contaminating the recovered T cells.”

An important discovery was finding out more about a family of signalling proteins called Phosphoinositide 3-kinases, or PI3Ks. These interact with T cells as they develop in the thymus and they are also used to transmit signals from receptors on the outside surfaces of the cells to the processes going on inside the cells. For instance, they tell the cell how to react when it encounters a particular pathogen.

The researchers in this study found out for the first time exactly which receptors the PI3Ks attach to on the T cell surface.

They also found that one particular member of the PI3K family, the PI3K-p110δ, sends signals from the pre-T cell receptor, a precursor of the T cell receptor, which detects foreign antigens in the body.

And another member of the family, the PI3K-p110γ transmits signals from a receptor known as CXCR4, which binds to the chemokine CXCL12 produced in the thymus.

Chemokines are thought to encourage immune system cells to travel towards an infections site, but this finding suggests CXL12 is also an important growth factor for maturing T cells.

Janas said that:

“Producing T cells without additional feeder cells requires a greater understanding of the growth factors normally provided by the thymus.”

She said discovering that CXCL12 is critical for immature T cell growth moves us closer to this goal:

“We have shown that immature T cells isolated from the thymus could only continue their developmental program when cultured in the presence of CXCL12 and another growth factor known as Notch-ligand. This is the first demonstration of T cell development in vitro that does not require supporting feeder cells,” explained Janas.

The researchers said these discoveries, which have now been patented, could also be useful for developing and testing new drugs where there is a need to screen for and understand how they might affect lymphocytes.

“Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4.”
Michelle L. Janas, Gabriele Varano, Kristjan Gudmundsson, Mamiko Noda, Takashi Nagasawa, and Martin Turner.
Journal of Experimental Medicine, Vol. 207, No. 1, 247-261, published online, 18th January 2010.
doi:10.1084/jem.20091430

Source: Babraham Institute.

Written by: Catharine Paddock, PhD