Research from the Babraham Institute, reported today in the Journal of Experimental Medicine, provides new insights into how our immune system produces T cells, a type of white blood cell that is an essential part of the body's immune surveillance system for fighting infection. The findings pave the way for a new means of making purified T cells, which gets over one of many hurdles faced in the use of T cells in regenerative medicine and transplantations, and in addition will open up new avenues of research and applications in drug and toxicity testing in industry.
This international collaboration of immunologists draws together academic and commercial researchers from the UK, Japan, GlaxoSmithKline USA and a Da Vinci exchange student from Italy. It reveals for the first time how immature T cells can be grown without the need for supporting "feeder" cells - these cannot be easily separated from T cell preparations, reducing their suitability for transplantation in the clinic. This may advance the field of regenerative medicine.
The discovery will enable scientists to ask fundamental questions about the immune system. Dr Martin Turner a Group Leader and Head of Babraham's Laboratory of Lymphocyte Signalling and Development, who led the research team said, "Studying how T cells develop helps us to understand healthy development, how T cells acquire specialised functions and what factors can cause lymphomas or other devastating illnesses. A goal of research in the field of regenerative medicine is T cell reconstitution for therapeutic purposes."
"One of the challenges for the scientific community is to reproduce the process of T cell development in the laboratory", said Dr Michelle Janas, lead author on the paper. "This technology could enable the production of T cells for clinical applications such as their transplantation into immuno-compromised individuals."
T cells develop in the thymus from progenitor cells recruited from the bone marrow. It is a complicated process requiring many biochemical signals and growth factors which bind to T cells. This binding transmits signals inside the cell causing genetic changes that are required to produce mature, active T cells capable of detecting foreign bodies - viruses, bacteria or fungi and mounting an appropriate attack.
Thymic function and T cell development is most active in early life but around the onset of puberty, the thymus starts shrinking and fewer T cells are made as we age. This progressive deterioration normally has little effect on healthy people. However, in the event of chemo/radiotherapy or infections like HIV/AIDS, the body's ability to replace T cells is severely compromised resulting in an abnormally low level of lymphocytes (T cell lymphopenia). Even after bone marrow transplant, T cell numbers to do not recover for at least two years. This decrease in thymic output also reduces the diversity of T cells patrolling our systems, leaving individuals vulnerable to opportunistic infection. This discovery at Babraham, an institute of the Biotechnology and Biological Sciences Research Council (BBSRC), may facilitate the production of pure tailor made T cells for transplantation.
Central to the team's discovery is a family of signalling proteins called Phosphoinositide 3-kinases, or PI3Ks, and their interaction with T cells as they mature in the thymus. PI3Ks are also used by cells to transmit signals from receptors on their outside to the machinery inside to dictate how the cell should react, for example when a T cell recognises the presence of a pathogen. However, the receptors to which each of these molecules were associated had, until now not been identified.
This study reveals that PI3K-p110d transmits signals from the pre-T cell receptor, a precursor of the T Cell Receptor, which detects foreign antigens in the body. Another signalling molecule called PI3K-p110g transmits signals from a receptor known as CXCR4, which binds to the chemokine CXCL12 produced in the thymus. Chemokines conventionally stimulate cells of the immune system to move (chemotaxis) to a site of infection, however, these findings indicate that CXCL12 is an important growth factor for developing T cells.
Dr Janas added, "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. Producing T cells without additional feeder cells requires a greater understanding of the growth factors normally provided by the thymus. The discovery that CXCL12 is critical for immature T cell growth brings us a step closer to achieving 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."
These patented discoveries could also be beneficial and highly valuable to the field of drug discovery and toxicology, where reliable methods to screen and understand the mode of action of pharmacological reagents on lymphocytes are sought, and in a clinical setting where sources of purified T cells free of contaminating accessory cells are required for transplantation purposes.