Regulatory T (Treg) cells in mice can lose lineage identity and acquire proinflammatory functions, but whether human Treg cells are similarly susceptible to cytokine-driven destabilization remains unclear. Here we established an in vitro model of human Treg cell destabilization defined by silencing of the lineage-specifying transcription factor FOXP3, loss of suppressive function and acquisition of proinflammatory activity. Single-cell chromatin accessibility and transcriptomic profiling revealed a genome-wide increase in accessibility at AP-1-binding sites, including a putative regulatory element distal to IRF4. Increased accessibility at this element correlated with increased IRF4 expression during Treg cell destabilization, and its excision conferred resistance to inflammatory cytokine-induced reprogramming. Conversely, forced expression of IRF4 together with BATF promoted Treg cell destabilization. These data identify a distal IRF4 regulatory element as a critical node enabling heightened AP-1-IRF4 cooperative activity to drive Treg cell destabilization, with implications for the design of more stable and effective Treg cell-based therapies.
Patrick Ho, Alexander Vu, Joey C. Leung et al.· Nature Immunology· 1 citation
We hypothesized that combined blockade of CD28 and interleukin-6 would favor regulatory T cells (Tregs) and prevent rejection in a novel calcineurin inhibitor-free immunosuppression regimen. In CTOT-24, a multicenter, prospective, phase I/II, pilot trial, live donor kidney transplant recipients received lulizumab pegol, a novel anti-CD28 domain antibody, and tocilizumab, an anti-IL-6R antibody, for 3 months followed by belatacept and tocilizumab for 3 months. All subjects received anti-thymocyte globulin, steroids, and mycophenolate mofetil or everolimus. The primary endpoint was the proportion of subjects free of biopsy-proven acute rejection at 6 months post-transplantation. Of eight treated subjects, five discontinued the study therapy prematurely for early acute T cell-mediated rejection (TCMR), severe neutropenia, and subject preference; three completed the regimen without rejection and remained on belatacept, MMF, and prednisone with mean estimated glomerular filtration rate 85.63 ml/min/1.73 m2 at 2 years post-transplantation. There were no cases of antibody-mediated rejection, death or graft loss. Flow cytometric analyses showed no increase in circulating Tregs under the study regimen and no differences between rejectors and non-rejectors. We conclude that a regimen of combined CD28 and IL-6 blockade prevented rejection in only a minority and that alternative strategies are needed to promote Tregs under CD28 blockade. NCT04066114.
S. Chandran, Qizhi Tang, J. Leung et al.· American Journal of Transpla...· 0 citations
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