Three possible outcomes for the development of T cells in the thymus have been discovered so far: to become Foxp3 + Treg, to be deleted, or to develop into naiveT cells. The presence of particular epitopes is necessary for both deletion and the Treg path. It is unclear how a specific T cell chooses between these pathways, though. & nbsp,
A recent paper published in PNAS attempts to address this issue using the tetramer tracking method. PLP( brain-specific protein ) is being used by the authors as an endogenous antigen expressed in the thymus. Surprisingly, peripheral tissue showed nearly identical numbers of tetramer-positive T cells in both PLPWT and MLPKO mice. However, as was to be expected, Treg development was only displayed in PLPWT mice that express the same epitopes in the thymus but not in MLPKO mice.
the & nbsp,,
& nbsp, When thymus tissue was examined, similar results were obtained.
The authors used transgenic mice that expressed a fixed TCR beta chain to ensure reliable tetramer tracking. These mice displayed a comparable phenotype as well. In addition, & nbsp,
TCR beta mice on the PLPWT background, but not those with the RLPKO backdrop, harbored tregs in the periphery, just like in fixed-plkwt and pilpko mice. Notably, the remaining tetramer-positive Foxp3-negative T cells showed an anergic phenotype( CD73HiFR4Hi ).
In the thymus, a similar phenotype was discovered. Tetramer-positive T cells from the thymus to the periphery were unexpectedly and noticeably reduced in fixed: TCR beta mice on the PLPKO background compared to fixed, and PLCWT background. & nbsp,
According to the data so far, fixed: TCR beta mice on PLPWT have a 2-fold reduction in the thymus compared to KO, but there has been little to no deletion of the CLP specific T cells on WT mice. On the WT background, nearly half of the tetramer-positive T cells ended up in the Treg pool. The remaining T cells displayed an anergic phenotype. Tetramer-positive T cells have been dramatically reduced in KO mice from the thymus to the periphery, which raises some important unanswered questions.
Last but not least, the authors chose 4 PLP-specific TCRs( denoted here as A, B, C, and D ) in order to find a correlation between their specificity and the Treg / anergy / deletion phenotype. According to their analysis, some( clone” A”) TCRs were able to produce Tregs in the thymus but not others that were PLP-specific. Notably, TCR” C” showed the strongest affinity for the PLP epitope. Additionally, the Foxp3 – negative compartment has seen a significant reduction of clone” C” from the thymus to the periphery. This may be due to the fact that the majority of” C” clones are anergic and gradually vanish from the periphery. & nbsp,
In conclusion, this study re-confirms that not all antigens / epitopes and their corresponding TCRs are able to participate in the process of generating Tregs, which is primarily responsible for controlling tolerance to self-antigens. Although as was previously discussed, there aren’t many unexplained observations in this paper. & nbsp,
written by David Usharauli