Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.DOI: http://dx.doi.org/10.7554/eLife.10066.001

Regulatory T cells (Treg) are a subpopulation of T cells that maintain tolerance to self and limit other immune responses. They achieve this through different mechanisms including the release of extracellular vesicles (EVs) such as exosomes as shown by us, and others. One of the ways that Treg derived EVs inhibit target cells such as effector T cells is via the transfer of miRNA. Another key target for the immunoregulatory function of Tregs is the dendritic cells (DCs). In this study we demonstrate directly, and for the first time, that miRNAs are transferred from Tregs to DCs via Treg derived EVs. In particular two miRNAs, namely miR-150-5p and miR-142-3p, were increased in DCs following their interaction with Tregs and Treg derived exosomes. One of the consequences for DCs following the acquisition of miRNAs contained in Treg derived EVs was the induction of a tolerogenic phenotype in these cells, with increased IL-10 and decreased IL-6 production being observed following LPS stimulation. Altogether our findings provide data to support the idea that intercellular transfer of miRNAs via EVs may be a novel mechanism by which Tregs regulate DC function and could represent a mechanism to inhibit immune reactions in tissues.

SummaryMicroRNA (miRNA) are small, non-coding RNA molecules that have been linked with immunity through regulating/modulating gene expression. A role for these molecules in T-cell and B-cell development and function has been well established. An increasing body of literature now highlights the importance of specific miRNA in dendritic cell (DC) development as well as their maturation process, antigen presentation capacity and cytokine release. Given the unique role of DC within the immune system, linking the innate and adaptive immune responses, understanding how specific miRNA affect DC function is of importance for understanding disease. In this review we summarize recent developments in miRNA and DC research, highlighting the requirement of miRNA in DC lineage commitment from bone marrow progenitors and for the development of subsets such as plasmacytoid DC and conventional DC. In addition, we discuss how infections and tumours modulate miRNA expression and consequently DC function.

The developmental pathways of regulatory T cells (Treg) generation in the thymus are not fully understood. Here, we reconstituted thymic development of Zap70 deficient thymocytes with a tetracycline inducible Zap70 transgene to allow temporal dissection of Treg development. We find that Treg develop with distinctive kinetics, first appearing by day 4 amongst CD4 single positive (SP) thymocytes. Accepted models of CD25+FoxP3+ Treg selection suggest development via CD25+FoxP3− CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25− FoxP3+ cells that are highly efficient at maturing to CD25+FoxP3+ cells in response to IL-2. CD25− FoxP3+ cells more closely resembled mature Treg both with respect to kinetics of development and avidity for self peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25−FoxP3+ cells were IL-15 dependent while generation of CD25+FoxP3+ specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, while IL-2 was of exclusively from haemopoetic cells that depended on intact CD4 lineage development but not either antigen experienced or NKT cells.

Summary Solid organ transplantation remains the treatment of choice for end‐stage organ failure. Whilst the short‐term outcomes post‐transplant have improved in the last decades, chronic rejection and immunosuppressant side effects remain an ongoing concern. Hematopoietic stem cell transplantation is a well‐established procedure for the treatment of patients with haematological disorders. However, donor T cells are continually primed and activated to react against the host causing graft‐versus‐host disease (GvHD) that leads to tissue damages and death. Regulatory T cells (Tregs) play an essential role in maintaining tolerance to self‐antigens, preventing excessive immune responses and abrogating autoimmunity. Due to their suppressive properties, Tregs have been extensively studied for their use as a cellular therapy aiming to treat GvHD and limit immune responses responsible for graft rejection. Several clinical trials have been conducted or are currently ongoing to investigate safety and feasibility of Treg‐based therapy. This review summarizes the general understanding of Treg biology and presents the methods used to isolate and expand Tregs. Furthermore, we describe data from the first clinical trials using Tregs, explaining the limitations and future application of these cells.

Exosomes are extracellular vesicles released by many cells of the body. These small vesicles play an important part in intercellular communication both in the local environment and systemically, facilitating in the transfer of proteins, cytokines as well as miRNA between cells. The observation that exosomes isolated from immune cells such as dendritic cells (DCs) modulate the immune response has paved the way for these structures to be considered as potential immunotherapeutic reagents. Indeed, clinical trials using DC derived exosomes to facilitate immune responses to specific cancer antigens are now underway. Exosomes can also have a negative effect on the immune response and exosomes isolated from regulatory T cells (Tregs) and other subsets of T cells have been shown to have immune suppressive capacities. Here, we review what is currently known about Treg derived exosomes and their contribution to immune regulation, as well as highlighting their possible therapeutic potential for preventing graft rejection, and use as diagnostic tools to assess transplant outcome.

Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the in vivo distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the in vivo biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.

Regulatory T cells (Tregs) are a subpopulation of CD4 + T cells with a fundamental role in maintaining immune homeostasis and inhibiting unwanted immune responses using several different mechanisms. Recently, the intercellular transfer of molecules between Tregs and their target cells has been shown via trogocytosis and the release of small extracellular vesicles (sEVs). In this study, CD4 + CD25 + CD127 lo human Tregs were found to produce sEVs capable of inhibiting the proliferation of effector T cells (Teffs) in a dose dependent manner. These vesicles also modified the cytokine profile of Teffs leading to an increase in the production of IL-4 and IL-10 whilst simultaneously decreasing the levels of IL-6, IL-2, and IFNγ. MicroRNAs found enriched in the Treg EVs were indirectly linked to the changes in the cytokine profile observed. In a humanized mouse skin transplant model, human Treg derived EVs inhibited alloimmune-mediated skin tissue damage by limiting immune cell infiltration. Taken together, Treg sEVs may represent an exciting cell-free therapy to promote transplant survival.