MRC National Institute for Medical Research, London
Science for Health
What happens if the thymus stops producing T cells?
20 June 2008
- What happens if the thymus stops producing T cells?
- What is the "life expectancy" of peripheral T cells?
- What can we learn about homeostasis and the regulation of pool sizes in the immune system?
NIMR scientists show how the absence of thymic function compromises replenishment and survival of the naïve CD4 T cell. The research is published in PNAS.
Regulation of cell numbers is an important principle in biology. In the immune system the number of peripheral lymphocytes is under tight homeostatic control and homeostatic principles safeguard independent co-existence of naïve and memory T cells to ensure on the one hand preservation of a polyclonal repertoire to meet new pathogen challenges and on the other hand a memory population capable of reacting quickly to previously encountered pathogens.
Since naïve T cells cannot be maintained in the periphery by division, but depend on continuous thymic export for replenishment of senescent cells, we wanted to investigate the consequences of thymus ablation for the maintenance of the peripheral T cell repertoire. In order to avoid surgical trauma, we used an approach of genetic thymectomy through conditional gene ablation of the recombinase (Rag) gene to study the decay of peripheral T cells. Induction of Rag ablation was efficient and complete leading to cessation of T cell production within 3-4 weeks. The decay of peripheral T cells was delayed for another 2-3 weeks and was entirely due to loss of naïve T cells. Memory and regulatory T cells did not disappear suggesting that these cells can maintain their numbers by homeostatic proliferation. Naïve CD4 T cells disappeared much more rapidly than naïve CD8 T cells. This was not due to an intrinsically different life span, but was caused by activation of CD4 T cells due to an increase in the gut derived microbial load in the absence of thymic output, indicating that replenishment with cells from the thymus seems to be required to maintain efficient gut mucosal defense.
The absence of thymic function therefore compromises replenishment and survival of the naïve CD4 T cell repertoire due to chronic activation. Such a scenario may play a role in the aging immune system and chronic viral infection, such as HIV infection and contribute to loss of CD4 T cells and impaired immune function. The research also has implications for generating novel animal models that may help to understand the complex regulatory networks of immune subsets in an intact organism.
This research was also a major achievement for Christine Bourgeois, a former senior postdoc at NIMR who has now established her own lab in Paris. It is also another example of cutting edge, intramural research being conducted at NIMR.
Original article
The research findings are published in full in:
Christine Bourgeois, Zhenyue Hao, Klaus Rajewsky, Alexandre J. Potocnik, and Brigitta Stockinger
Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen
PNAS, Epub ahead of print Pubmed abstract
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