A neonatal temporal window for thymic epitope-specific Foxp3+ Treg formation

Without a doubt, the most significant immune cell type is the thymus-derived Foxp3 + Tregs. Surprisingly, not much has been done to determine the specificity of their antigen. The fact that most scientists believed Tregs inhibited unwanted T cell responses antigen in a non-specific way is one reason for this lack of interest in studying it. They therefore argued against bothering with TCR specificity. However, more recently, they began to pay close attention to antigen-specificity of Tregs because it was evident that they had a superior, if not exclusive, therapeutic effect in animal models. In addition, & nbsp,

Therefore, any research that improves our knowledge of how antigen-specific Tregs form is extremely valuable. I’ll go over one such study from Eric Huseby’s lab at the University of Massachusetts Medical School in Worcester, Massachusetts, USA, which was published in Nature Immunology.

In this study, they used standard hybridoma technology and a library of 1, 750 different self-peptides to clone several hundred TCRs from Foxp3 + GFP + Tregs and screen their specificity in an in vitro IL-2 bioassay( it is amazing that so few labs have used this readily available approach ). About 17 peptides responded favorably. Peptyl arginine deiminase type IV( Padi492 – 105 ) and Adducin 2( Add2606 – 621 ) were the two peptides they decided to concentrate on. With the appropriate KO mice, TCR specificity for Padi492 – 105 or Add2606 – 621 was confirmed.

Curiously, they discovered that the thymic development of the Padi492 – 105 specific Tregs was time-restricted, and that after three weeks of pregnancy, their formation quickly decreased.

More importantly, both the initial formation of the Treg and its subsequent reduction were primarily caused by specific antigen expression.

However, even though the frequency of Padi492 – 105 & nbsp, specific Tregs both in the thymus and periphery initially decreased as a result of age, their absolute numbers were later maintained at the same level there. It’s crucial to emphasize this.

Notably, in chimera where only thymic stromal cells expressed specific epitope but not bone marrow derived cells, this age-related antigen-dependent Treg reduction could be reversed. It could imply that age-related decline in the formation of Padi492 – 105 specific Tregs is caused by dose effects or a specialized antigen-presentation pathway.

Additionally, only moderately potency responders were enriched in Tregs at the periphery( the highest potence T cells were lost in the thymus and the lowest power T cell ended up in Tconv spleen pool ) out of several Padi492 – 105 specific TCRs with varying antigen response potencies. This is conveniently too clean in my opinion.

Additionally, the authors discovered that self-MHC half-life( t1 / 2 ) was the trait formation that was most closely related to the TCR.

In conclusion, this study discovered a number of self epitopes that are responsible for mouse treg formation in the thymus, though this process is only active after birth. It is unclear why or how the cessation of treg formation is taking place in this thymus. Absolute numbers of these epitope-specific Tregs that seeded the periphery remained constant, which suggests that there may be a saturation feedback loop between the thymus and peripetriny that modifies treg numbers. The authors also propose that Treg formation could be predicted using only TCR: self-MHC dwell half-life( t1 / 2 ). However, dwell time is unable to account for their own observation of the age-related decline in treg formation. What has changed so drastically in the eighth week as opposed to the third week to upend dwell time? Additionally, a mechanism of bifurcation that has been demonstrated to occur independently of TCR affinity and determines deletion versus Treg formation at the single thymocyte level was not addressed in this paper. & nbsp,

These findings, for instance, may help to explain why some CD4 + TCR transgenic mice, like the marilyn CD4 ,+ TCR mouse, still harbor thymic Foxp3 + Treg formation despite not displaying it. It will miss the thymic phase because such mice are typically examined when they are adults( andgt, 8 weeks ). & nbsp,

written by David Usharauli