Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a "triggered exchange" mechanism favoring IL-2Rα(hi) Treg cells, creating a positive feedback loop for IL-2Rα(hi) cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ(hi) effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.
- MeSH
- autoimunitní nemoci imunologie MeSH
- interleukin-2 chemie genetika imunologie metabolismus MeSH
- kompetitivní vazba účinky léků MeSH
- lidé MeSH
- molekulární modely * MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- progrese nemoci MeSH
- proliferace buněk účinky léků MeSH
- protilátky chemie imunologie farmakologie MeSH
- průtoková cytometrie MeSH
- regulace genové exprese imunologie MeSH
- regulační T-lymfocyty cytologie účinky léků imunologie MeSH
- signální transdukce účinky léků MeSH
- T-lymfocyty - podskupiny cytologie účinky léků imunologie MeSH
- terciární struktura proteinů MeSH
- vazba proteinů účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
