Abstract
Human regulatory macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation. It is hypothesised that recipient CD4+ T cell responses are actively regulated through direct allorecognition of donor-derived Mregs. Here we show that human Mregs convert allogeneic CD4+ T cells to IL-10-producing, TIGIT+ FoxP3+-induced regulatory T cells that non-specifically suppress bystander T cells and inhibit dendritic cell maturation. Differentiation of Mreg-induced Tregs relies on multiple non-redundant mechanisms that are not exclusive to interaction of Mregs and T cells, including signals mediated by indoleamine 2,3-dioxygenase, TGF-β, retinoic acid, Notch and progestagen-associated endometrial protein. Preoperative administration of donor-derived Mregs to living-donor kidney transplant recipients results in an acute increase in circulating TIGIT+ Tregs. These results suggest a feed-forward mechanism by which Mreg treatment promotes allograft acceptance through rapid induction of direct-pathway Tregs.
Highlights
Human regulatory macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation
Addition of 1-L-MT to cocultures, but not 1-D-MT, significantly reduced TIGIT+ T cell frequency (Fig. 8g). Mregs expressed both CD112 (PVRL2) and CD155 (PVR), which are ligands of TIGIT (Fig. 8h). These findings show that Mregs induce TIGIT expression in allogeneic T cells through an IDOdependent mechanism, as well as providing TIGIT ligands, which might explain the high level of IL-10 production by miTregs
Expansion of TCRVβ13.1+ T cells was still detectable at the time of follow-up and, more surprisingly, we found the TCRVβ13.1+ CD4+ T cell compartment was enriched for TIGIT+ FoxP3+ Tregs
Summary
Human regulatory macrophages (Mreg) have shown early clinical promise as a cell-based adjunct immunosuppressive therapy in solid organ transplantation. Preclinical experiments in a heterotopic mouse heart transplant model demonstrated that intravenous (i.v.) injection of donorstrain Mregs conferred long-term transplant acceptance to nonimmunosuppressed, fully allogeneic recipients[12] This allograft-protective effect was not due to alloantigen exposure but depended upon Mregs expressing inducible nitric oxide synthase. Following i.v. injection into mice, allogeneic Mregs rapidly accumulated in lung, liver and spleen, but not in lymph nodes, where a proportion of transferred Mregs persisted for up to 4 weeks These experiments showed that living Mregs exerted a graft-protective effect that endured beyond their lifespan, which was likely mediated by recipient T cells. Mouse and human Mregs suppress allogeneic T cell proliferation and effector functions in vitro, it remains controversial whether they can control recipient alloimmune responses in vivo through direct interaction of transferred cells with recipient T cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
