Ethan Shevach: Tregs - ready for the clinic?

[@simonsteen-andersen3181]

Expression of IL12RB2 is part of IL-2-signaling as well as of the functional synergy of IL-2 and IL-12 whereby il-2-induced upregulation of CD25 and activation of STAT5 lead to strong upregulation of IL12RB2, suggesting that the interdependent upregulation of both receptors is essential for efficient proliferation. In the IL12RB2-/- mice, it was shown that their T-cells lack proliferation as well as present with 100 times less efficient Treg-mediated suppression than WT mice. Interestingly, JMJD3 has been shown to bind to IL12RB2 on three locations on the introns, which could suggest the importance of IL12RB2/JMJD3 signaling for the necessary changes in the epigenetic landscape which provide chromatin accessability for transcription factors in order to aquire a Treg specific gene expression.... Furthermore, IL12RB2 knockout is just as capable of inhibiting p38 mapk as a pharmacological mapk p38 inhibitor, and a functional IL12RB2 is capable of activating p38 mapk independently of IL12RB1. T-cell mediated CD40Ligand signaling and maturation of DCs is necessary for the DC to become a sufficient IL-12p70 producer, which is also shown to depend on p38 mapk. Could IL12RB2 be necessary for the recruitment of p38 mapk via epigenetic chromatin remodeling and the intergration of CD40L-mediated DC production of IL-12p70! Interestingly, this T-cell mediated p38 mapk signaling pathway which is necessary for the transition from innate type 1 IFN signaling into the adaptive IL-12-induced IFN-gamma circuit,- could be important for maintaining the immune tolerance to CpG DNA according to studies showing p38 mapk to be an important factor for tolerance. Could this pathway give rise to some of the paradoxes where mice models, with natural tolerance to unmethylated CpG DNA is difficult to fully understand, because in order to study this phenomena one would need a human model/patient with mutatations in the exon/intronic regions, maybe on exon 1-3), deleting the locations necessary for the binding of JMJD3 to IL12RB2 and for the recruitment of p38 mapk and the molecular mRNA remodeling during T-cell activation?

[@simonsteen-andersen3181]

What could the role of IL12RB2 be, which are also expressed on thymic epithelial cells where also AIRE is expressed? The mice model of IL12RB2-/- develops spontaneous autoimmunity with organ specific and systemic immune-complex infiltrations and Lupus-like vasculitis? Furthermore, this model is used to study autoimmunity triggered by self-antigen vaccination....

[@robfryderykchopin8505]

you mention its impossible to get antigen specific t-regs. Why not use the same approach that TEVA used with the ms drug copaxone. its a peptide salt comprised of the 4 amino acids that make up the human myelin sheath. once injected, it stimulates myelin specific T-regs.

[@mirnamirna1547]

Interesting but i didn't understand a lot of what he said if one could get in touch and explain this to me i'll be grateful