In Vivo Attenuation of Antibody-Mediated Acute Renal Allograft Rejection by Ex Vivo TGF-β-Induced CD4+Foxp3+ Regulatory T Cells

Antibody-mediated rejection (AMR) has emerged as the major cause of renal allograft dysfunction, and more effective strategies need to be explored for improving transplant outcomes. Regulatory T cells (Tregs), consisting of at least natural and induced Treg subsets, suppress effector responses at multiple levels and play a key role in transplantation tolerance. In this study, we investigated the effect of induced Tregs (iTregs) on preventing antibody-mediated renal injury and rejection in a mouse model. We observed that infusion of iTregs markedly attenuated histological graft injury and rejection and significantly improved renal allograft survival. iTregs exhibited a comprehensive ability to regulate immunological disorders in AMR. First, iTreg treatment decreased the levels of circulating antidonor antibody and the antibody deposition within allografts. Second, iTregs significantly reduced cell infiltration including CD4+ T cells (including Th1, Th17, and Tfh), CD8+IFN-γ+ cells, natural killer cells, B cells, and plasma cells, which are involved in the process of AMR. Our results also highlight a predominance of M1 macrophage infiltration in grafts with acute AMR, and M1 macrophage could be reduced by iTreg treatment. Collectively, our data demonstrate, for the first time, that TGF-β-induced Tregs can attenuate antibody-mediated acute renal allograft injury through targeting multiple effectors. Thus, use of iTregs in prevention of AMR in clinical practice could be expected

Negligible Effect of Sodium Chloride on the Development and Function of TGF-β-Induced CD4+ Foxp3+ Regulatory T Cells

Summary: High-salt diets inhibit the suppressive function of thymus-derived natural regulatory T cells (tTreg). Transforming growth factor β (TGF-β)-induced ex vivo regulatory T cells (iTreg) comprise another Treg subset that exhibits similarities and differences with tTreg. Here, we demonstrate that iTregs are completely stable and fully functional under high salt conditions. High salt does not influence the development, differentiation, and functional activities of iTreg but affects Foxp3 stability and function of tTreg in vitro and in vivo. In addition, high salt does not significantly change the transcription profiles of the iTreg signature or pro-inflammatory genes. Therefore, we conclude that iTreg, unlike tTreg, are stable and functional in the presence of high salt. Our findings provide additional evidence that iTreg may have different biological features from tTreg and suggest a greater potential for clinical utility in patients with autoimmune diseases, in which the complicated role of environmental factors, including diet, must be considered. : Luo et al. show that high salt does not affect the characteristics of TGF-β-induced regulatory T cells (iTregs). iTregs are stable and functional in the presence of high salt during autoimmune responses. Keywords: TGF-β-induced regulatory T cells, iTreg, thymus-derived natural regulatory T cells, tTreg, induced regulatory T cells in the periphery, pTreg, sodium chloride, Th1, Th17, coliti

Neuropilin-1 Identifies a New Subpopulation of TGF-β-Induced Foxp3 Regulatory T Cells With Potent Suppressive Function and Enhanced Stability During Inflammation

CD4Foxp3 regulatory T cells (Tregs) play a crucial role in preventing autoimmunity and inflammation. There are naturally-derived in the thymus (tTreg), generated extrathymically in the periphery (pTreg), and induced culture (iTreg) with different characteristics of suppressiveness, stability, and plasticity. There is an abundance of published data on neuropilin-1 (Nrp-1) as a tTreg marker, but little data exist on iTreg. The fidelity of Nrp-1 as a tTreg marker and its role in iTreg remains to be explored. This study found that Nrp-1 was expressed by a subset of Foxp3CD4T cells in the central and peripheral lymphoid organs in intact mice, as well as in iTreg. Nrp-1iTreg and Nrp-1iTreg were adoptively transferred into a T cell-mediated colitis model to determine their ability to suppress inflammation. Differences in gene expression between Nrp-1 and Nrp-1iTreg were analyzed by RNA sequencing. We demonstrated that the Nrp-1 subset of the iTreg exhibited enhanced suppressive function and stability compared to the Nrp-1 counterpart both and , partly depending on IL-10. We found that Nrp-1 is not an exclusive marker of tTreg, however, it is a biomarker identifying a new subset of iTreg with enhanced suppressive function, implicating a potential for Nrp-1iTreg cell therapy for autoimmune and inflammatory diseases