Bruce Hall: Antigen specific CD4+CD25+Foxp3+Treg generated from natural Treg (nTreg)

Re-establishing immune tolerance requires antigen specific CD4+CD25+Foxp3+Treg not nTreg which are non-antigen specific. We studied pathways for activation of nTreg antigen, and identified one activated by Th1 and another by Th2 cytokines. The initial activation by antigen respectively requires IL-2 or IL-4. Within days, nTreg express receptors for other lineage cytokines, respectively IFN-γ and IL-12 or IL-5.
The IL-2 and antigen activated nTreg we call Ts1 cells, and they express CD25, Foxp3, IL-5, IFNGR, IL-12Rβ2, but no IL-2, t-bet, IFN-γ or IL-5Rα. Antigen with IL-12, in the absence of IL-2, activates Ts1 cells to Th1-like Treg that suppress in an antigen specific manner, and delay fully allogeneic rejection. Th1-like Treg express Foxp3, t-bet, IFN-γ, IL-12Rβ2, IFNGR and IL-5, but no IL-2. Similar Th1-like Treg can be induced by IFN-γ and IL-27.
The IL-4 and antigen induced nTreg we call Ts2. Ts2 express CD4, Foxp3, IFN-γ, IL-5Rα, but no IL-2, IL-4, IL-5, Gata-3 IFNGR or IL-12Rβ2. Reculture of Ts2 cells with IL-5 and antigen, in the absence of IL-4, induces Th2-likeTreg expressing CD25,Foxp3,IL-5Rα,IL-4,IL-5,IRF4, but not T-bet,IL-2,IFN-γ, IFNGR.
Ts1 and Ts2 cells can be generated in vitro in 3 days, are antigen specific and have greater than 10x suppression in vitro and in vivo than nTreg. Th1 and Th2 like Treg can be generated in vitro in 7 days and have 1000x greater capacity to suppress in vitro than nTreg. Therapy with IL-5 promotes Ts2 and Th2 like Treg and can suppress auto and alloimmune responses. These pathways can generate antigen specific Treg in vitro for use in therapy. Therapy with IL-5 enhances the Th2 pathway to promote antigen specific tolerance. We will discuss the potential therapeutic options for utilizing these antigen specific Treg activation pathways to restore tolerance.