In order to effectively prevent disease, the immune system must be able to distinguish between self and non-self, and to selectively target the latter. The process that removes immune cells that would otherwise react to the body – engage in friendly fire – is called negative selection.
A new paper published in this week's PLoS Biology, the online open access journal, investigates the inner mechanics of the thymus, the organ that creates the foot soldiers of the immune system. The paper, by Sejin Ahn and colleagues, helps shed light on the timing and regulation of negative selection, a crucial developmental process.
The thymus creates T cells, white blood cells that destroy harmful material as part of the immune response to pathogens. Many more immature T cells are created than are allowed to develop, and the filtering processes – which select only those immature cells that can be useful – occurs within the thymus. The thymus is roughly divided into two main regions, the medulla and the cortex. It has previously been unclear whether the cortex is involved in negative selection, or whether this process is restricted to the medulla.
The new paper, a collaboration between researchers from the US, Korea and the UK, has changed this. The authors have genetically engineered mice to contain an antigen, LacZ, in only a small fraction of the cells of the cortex and nowhere else in the body. They found that any T cells that were programmed to attack LacZ were absent from the mature mice. As the T cells could only have been exposed to LacZ in the cortex, this is strong evidence the cortex has removed them before they reach the rest of the body. Therefore the cortex also has a role in negative selection and significantly tolerizes the developing T cells with impressive efficiency.
This research allows a much clearer understanding of the internal mechanics of the thymus, and how negative selection might work.
- Ahn S, Lee G, Yang SJ, Lee D, Lee S, et al. TSCOT+ Thymic Epithelial Cell-Mediated Sensitive CD4 Tolerance by Direct Presentation. PLoS Biol, 2008; 6(8): e191 DOI: 10.1371/journal.pbio.0060191
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