The most significant cell type in the immune system are regulatory T cells, also known as Tregs, which express the transcription factor Foxp3. Without them, the immune system as a whole malfunctions. As a result, the body simply passes away quickly.
The TCR signaling and IL-2 are necessary for the Tregs to develop in the thymus. A very wide range of epitopes, including those from peripheral tissues like the pancreas or prostate, are expressed by the thymus. Proto-Treg is sensitive to local IL-2 due to the high-affinity interaction between TCR and epitope / MHC II, which is a necessary step to complete the Treg formation loop.
But which cell delivers the essential IL-2 to proto-Tregs? Although there hasn’t been much agreement on this, a recent paper from Sasha Rudensky’s lab in the Journal of Experimental Medicine suggests that the primary source of thymic IL-2 needed for Treg development is CD4 + T cells and CD25 + Foxp3 – CD4. + single-positive( SP ).
In order to conduct this study, they used an IL-2 reporter mouse, in which cells that express or have a history of expressing the gene were genetically labeled and analyzed. They discovered that TCRbeta, which expresses the CD4 + population, was the only expression for IL-2.
The population of mature CD4 SP and CD25 + Foxp3-CD4 + T cells produced the most IL-2. It should be noted that the CD25 + Foxp3 – T cell population includes proto-Tregs.
It’s interesting to note that the authors also found mature Tregs with IL-2 expression history. It suggests that the process of bifurcation between Tregs and IL-2 producers is stochastic.
As anticipated, IL-2 and TCR signaling were crucial for the formation of Tregs. It is possible to explain a” bystander” effect on Foxp3 upregulation on antigen-independent proto-Tregs ( Vbeta 8 – T cells ) by pointing out that these T cell types were likely TCR activated in vivo prior to harvesting for an experiment in vitro.
Based on these findings, the authors proposed the following theory: among mature SP CD4 T cells, a small pool produces IL-2, which, when combined with high-affinity TCR / epitope interaction and CD25 upregulation, encourages the formation of Foxp3 + Tregs in either an autocrine or paraprine way. We can infer that those IL – 2 producing T cells are auto – reactive because the thymus is expressing self epitopes.
The following queries are still unanswered:
1. What factors into the producer or deletion pathways Treg, IL-2? For high-affinity TCR + CD4 SP cells, all three options are available.
2. 2. Do Tregs and IL – 2 producers share the same TCR specificity?
3. 3. What cells deliver IL-2 to the periphery’s trenches?
4.. 4. Is the TCR / epitope for the IL – 2 delivery event specific or not?
We recently released a brand-new model called SPIRAL that offers solutions to these issues. The SPIRAL is founded on the idea of epitope cross-reactivity.
written by David Usharauli
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