Highlight Publication January 2010

Janas M, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M
Thymic development beyond β-selection requires phosphatidylinositol 3-kinase activation by CXCR4
Journal of Experimental Medicine
http://dx.doi.org/10.1084/jem.20091430

Lay Summary

T lymphocytes are an essential component of the adaptive immune system, providing protection against pathogenic infections as well as detecting and destroying early tumour cells. T cells develop in the thymus from multipotent progenitor cells that are recruited from the bone marrow. Once in the thymus, these cells undergo a multistep developmental program to become fully functional T cells that can recognise and respond to foreign antigens. At maturity, the T cells exit the thymus to become part of the body’s immune surveillance system.

As T cells move through the thymus environment they bind to different growth factors. This binding transmits signals inside the cell which instigates genetic changes that are required for continued T cell development. One of the major signalling molecules involved in this process is called phosphatidylinositol 3-kinase (PI3K). Previous work in the laboratory had shown that two distinct classes of PI3K, class IA (p110δ) and class IB (p110γ), were critical for signal transduction in developing T cells, however, the receptors to which each of these molecules were associated had not been defined.

In this study we show that PI3K-p110δ transmits signals from the pre-T cell receptor (preTCR). The preTCR is precursor form of the T Cell Receptor, which is responsible for detecting foreign antigens in the body. PI3K-p110γ was found to transmit signals from a receptor known as CXCR4. CXCR4 binds to the chemokine CXCL12, which is produced in the thymus. Chemokines are conventionally considered to promote the movement of cells throughout the body; however our studies have shown CXCL12 to be an important growth factor for developing T cells.

One of the challenges for the scientific community is to be able to recapitulate the process of T cell development in the laboratory. This technology would allow for the generation of T cells which could be used for clinical applications, such as transplantation into immuno-compromised individuals. The generation of T cells in culture is currently possible, but it requires the use of supporting feeder cells. The feeder cells act by mimicking the thymus environment but come with the disadvantage of contaminating the recovered T cells. The generation of 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. Indeed, we have shown that immature T cells isolated from the thymus were able to continue their developmental program when cultured only in the presence of CXCL12 and Notch-ligand (another, previously defined, growth factor). This is the first demonstration of T cell development in vitro that does not require supporting feeder cells.

Press release relating to the publication

Career History of Michelle Janas

Michelle Janas completed her PhD studies at the Walter and Eliza Hall Institute of Medical Research in Melbourne Australia, where she studied signalling requirements for B lymphocyte development. Thereafter Dr Janas joined the biotechnology company Ozgene Pty. Ltd as a senior scientist before returning to academic research at The Queensland Institute of Medical Research, Australia. Dr Janas joined the Laboratory of Lymphocyte Signalling and Development at Babraham in 2005 where she studies the signalling requirements for T cell development in the thymus.