TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity.

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-ß, 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.

First-in-Human Case Study: Multipotent Adult Progenitor Cells for Immunomodulation After Liver Transplantation.

Mesenchymal stem cells and multipotent adult progenitor cells (MAPCs) have been proposed as novel therapeutics for solid organ transplant recipients with the aim of reducing exposure to pharmacological immunosuppression and its side effects. In the present study, we describe the clinical course of the first patient of the phase I, dose-escalation safety and feasibility study, MiSOT-I (Mesenchymal Stem Cells in Solid Organ Transplantation Phase I). After receiving a living-related liver graft, the patient was given one intraportal injection and one intravenous infusion of third-party MAPC in a low-dose pharmacological immunosuppressive background. Cell administration was found to be technically feasible; importantly, we found no evidence of acute toxicity associated with MAPC infusions.

Caveats of mesenchymal stem cell therapy in solid organ transplantation.

In the past decade, therapeutic use of mesenchymal stem cells (MSCs) has increased dramatically. The weight of existing evidence supports that the short-term application of MSCs is safe and feasible; however, concerns remain over the possibility of unwanted long-term effects. One fundamental difference between MSCs and pharmacotherapy is that, once applied, the effects of cell products cannot be easily reversed. Therefore, a carefully considered decision process is indispensable before cell infusion. In addition to unwanted interactions of MSCs with the host immune system, there are concerns that MSCs may promote tumor progression or even give rise to cancer themselves. As animal models and first-in-man clinical studies have provided conflicting results, it is challenging to estimate the long-term risk of individual patients. In addition, most animal models, especially rodents, are ill-suited to adequately address questions over long-term side effects. Based on the available evidence, we address the potential pitfalls for the use of MSCs as a therapeutic agent to control alloimmune effects. The aim of this review was not to discourage investigators from clinical studies, but to raise awareness of the intrinsic risks of MSC therapy.

Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy.

The ultimate goal in transplantation medicine is the promotion of operational tolerance. Although Th cells of the Th17 type have been predominantly associated with rejection of allogeneic solid organ grafts, regulatory T (T(reg)) cells appear to foster operational tolerance. Induced T(reg) and Th17 cells have a higher lineage plasticity than has been recognized thus far. We found that when mesenchymal stem cells (MSCs) were used to induce long-term acceptance of allogeneic heart grafts in mice, the induction of T(reg) cells was preceded by development of a CD11b(hi)Gr1(int) myeloid-derived immunosuppressive cell-mediated Th17 response. Substantial suppression of Foxp3(+) T(reg) cell generation from retinoic acid receptor-related orphan receptor γ(-/-) T cells by MSCs revealed that retinoic acid receptor-related orphan receptor γ is a common factor in the differentiation of T(reg) and Th17 cells. Immunosuppressant mycophenolate mofetil treatment of enriched IL-17A(+) cells from MSC-primed allograft mouse recipients resulted in a reduction of IL-17A production and an increase in the Foxp3(+) T(reg) cell fraction. Furthermore, identification of IL-17A(+) Foxp3(+) double-positive and ex-IL-17-producing IL-17A(neg)Foxp3(+) T cells strongly argues for direct conversion of Th17 cells into T(reg) cells as the underlying mechanism of immune regulation in MSC-mediated allograft survival. The Th17 into T(reg) conversion identified in this study constitutes an important immunological mechanism by which MSC-induced myeloid-derived immunosuppressive cells mediate operational transplant tolerance. The possibility to create T(reg) cell-regulated operational tolerance in the absence of complete immune suppression provides strong clinical implications for cell therapy-assisted minimization protocols.

Human Peripheral CD4(+) Vδ1(+) γδT Cells Can Develop into αßT Cells.

The lifelong generation of αßT cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naïve and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naïve T cells, and recent research suggests that also αßT-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. γδT cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. γδT cells that express the Vδ1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4(+) peripheral Vδ1(+) γδT-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional αßT cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re-organization of the Vδ1(+) γδTCR into the αßTCR as a consequence of TCR-γ chain downregulation and the expression of surface Vδ1(+)Vß(+) TCR components, which we believe function as surrogate pre-TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered.