Behavior of recent thymic emigrant T cells supports 60 year old hypothesis

This week Journal of Experimental Medicine published new study that showed that recent thymic emigrant T cells are highly susceptible to tolerance upon antigen encounter in the periphery.

I selected to review this article because its topic underlies one of the fundamental questions of immunology, namely how T cells are tolerized to peripheral antigens [not expressed in the thymus]?

Let's start from the beginning. T cells generated in the thymus express T cell receptor (TCR) with all kind of specificity. Most of T cells specific for self-antigens are deleted within thymus. Thymus also express some of the peripheral antigens, such as insulin and other proteins, under the guidance of two genes AIRE and Fezl. However, it is conceivable that some of the peripheral antigens are not expressed at all in the thymus or are expressed too little to completely delete auto-reactive T cells. So what those auto-reactive T cells would do once they leave the thymus and encounter self-antigens in the periphery?  

So, this new study suggests that those young T cells leaving thymus for the first time [they are called recent thymic emigrants, RTEs] are highly sensitive to tolerization and display anergic phenotype when stimulated by antigen. Basically there is a "window of opportunity" for peripheral tolerance for RTEs. These results support the hypothesis proposed by Joshua Lederberg 1950s to save Burnet's clonal selection theory (though it was disappointing to see that this study did not refer to it).

To distinguish between RTEs and conventional naive T cells the authors used RAG2p-GFP mouse model that marks RTEs with GFP for ~3 weeks [after leaving thymus]. When OVA-specific RTEs and naive T cells were transferred in OVA-expressing hosts and later re-stimulated, RTEs showed less proliferation and less effector differentiation.

Functional changes in RTEs upon encountering specific antigen in the periphery was confirmed by absence or delay in development of diabetes in OVA-expressing hosts (OVA is expressed in pancreas).

RTEs were also more susceptible to suppression by Tregs.

Finally, the authors showed that if RTEs were exposed to peripheral antigens in context of inflammation (alum or CFA), then they could undergo full effector differentiation equal to that of conventional naive T cells.

In summary, this short paper suggests that RTEs and naive T cells are functionally distinct and that 3 weeks of post-thymus period play physiological role in peripheral tolerance.

I also want to highlight some of the deficiencies of this paper: 

1st, the authors did not test whether RTEs indeed "become" conventional naive T cells in 3 weeks after transfer in antigen-free hosts. For example, I would have transferred RTEs first in antigen-free host and then 3 weeks later transfer again those T cells into antigen-expressed hosts. Prediction would be that 2nd transfer T cells should behave as conventional naive T cells.    

2nd, the authors used alum and CFA immunization to recreate inflammatory context. However, antigen presentation and inflammation in the context of alum or CFA are quite different from inflammation in natural context such as infection. I would have used bacterial or viral infection and then transfer RTEs in infected hosts to see how more natural inflammatory context would have affected their behavior (later I was informed that such experiment was indeed done with the same outcome).

David Usharauli