A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFß activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

T cells use distinct topographical and membrane receptor scanning strategies that individually coalesce during receptor recognition.

During immune surveillance, CD8 T cells scan the surface of antigen-presenting cells using dynamic microvillar palpation and movements as well as by having their receptors preconcentrated into patches. Here, we use real-time lattice light-sheet microscopy to demonstrate the independence of microvillar and membrane receptor patch scanning. While T cell receptor (TCR) patches can distribute to microvilli, they do so stochastically and not preferentially as for other receptors such as CD62L. The distinctness of TCR patch movement from microvillar movement extends to many other receptors that form patches that also scan independent of the TCR. An exception to this is the CD8 coreceptor which largely comigrates in patches that overlap with or are closely adjacent to those containing TCRs. Microvilli that assemble into a synapse contain various arrays of the engaged patches, notably of TCRs and the inhibitory receptor PD-1, creating a pastiche of occupancies that vary from microvillar contact to contact. In summary, this work demonstrates that localization of receptor patches within the membrane and on microvillar projections is random prior to antigen detection and that such random variation may play into the generation of many individually composed receptor patch compositions at a single synapse.

Light-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks.

The molecular nanoscale organization of the surfaceome is a fundamental regulator of cellular signaling in health and disease. Technologies for mapping the spatial relationships of cell surface receptors and their extracellular signaling synapses would unlock theranostic opportunities to target protein communities and the possibility to engineer extracellular signaling. Here, we develop an optoproteomic technology termed LUX-MS that enables the targeted elucidation of acute protein interactions on and in between living cells using light-controlled singlet oxygen generators (SOG). By using SOG-coupled antibodies, small molecule drugs, biologics and intact viral particles, we demonstrate the ability of LUX-MS to decode ligand receptor interactions across organisms and to discover surfaceome receptor nanoscale organization with direct implications for drug action. Furthermore, by coupling SOG to antigens we achieved light-controlled molecular mapping of intercellular signaling within functional immune synapses between antigen-presenting cells and CD8+ T cells providing insights into T cell activation with spatiotemporal specificity. LUX-MS based decoding of surfaceome signaling architectures thereby provides a molecular framework for the rational development of theranostic strategies.

pH-Sensitive branched ß-glucan-modified liposomes for activation of antigen presenting cells and induction of antitumor immunity.

Induction of cellular immunity is important for effective cancer immunotherapy. Although various antigen carriers for cancer immunotherapy have been developed to date, balancing efficient antigen delivery to antigen presenting cells (APCs) and their activation via innate immune receptors, both of which are crucially important for the induction of strong cellular immunity, remains challenging. For this study, branched ß-glucan was selected as an intrinsically immunity-stimulating and biocompatible material. It was engineered to develop multifunctional liposomal cancer vaccines capable of efficient interactions with APCs and subsequent activation of the cells. Hydroxy groups of branched ß-glucan (Aquaß) were modified with 3-methylglutaric acid ester and decyl groups, respectively, to provide pH-sensitivity and anchoring capability to the liposomal membrane. The modification efficiency of Aquaß derivatives to the liposomes was significantly high compared with linear ß-glucan (curdlan) derivatives. Aquaß derivative-modified liposomes released their contents in response to weakly acidic pH. As a model antigenic protein, ovalbumin (OVA)-loaded liposomes modified with Aquaß derivatives interacted efficiently with dendritic cells, and induced inflammatory cytokine secretion from the cells. Subcutaneous administration of Aquaß derivative-modified liposomes suppressed the growth of the E.G7-OVA tumor significantly compared with curdlan derivative-modified liposomes. Aquaß derivative-modified liposomes induced the increase of CD8+ T cells, and polarized macrophages to the antitumor M1-phenotype within the tumor microenvironment. Therefore, pH-sensitive Aquaß derivatives can be promising materials for liposomal antigen delivery systems to induce antitumor immune responses efficiently.

Hypothesis: Immunotherapy by Selective Convalescent Blood Engineering to Stifle Diseases like COVID-19.

Current standard vaccine testing protocols take approximately 10-24 months of testing before a vaccine can be declared successful. Sometimes by the time a successful vaccine is out for public use, the outbreak may already be over. With no vaccine or antiviral drug available to treat the infected, we are left with the age-old methods of isolation, quarantine, and rest, to arrest such a viral outbreak. Convalescent blood therapy and covalent plasma therapy have often proved effective in reducing mortality, however, the role of innate and adaptive immune cells in these therapies have been overlooked. Antigen presenting cells (APCs), CD4+ T memory cells, CD8+ T memory cells, and memory B-Cells all play a vital role in sustainable defense and subsequent recovery. This report incorporates all these aspects by suggesting a novel treatment therapy called selective convalescent leukapheresis and transfusion (SCLT) and also highlights its potential in vaccination. The anticipated advantages of the proposed technique outweigh the cost, time, and efficiency of other available transfusion and vaccination processes. It is envisioned that in the future this new approach could serve as a rapid emergency response to subdue a pathogen outbreak and to stop it from becoming an epidemic, or pandemic.

Peptide-Modified Biopolymers for Biomedical Applications.

Polymeric biomaterials have been used in a variety of applications, like cargo delivery and tissue scaffolding, because they are easily synthesized and can be adapted to many systems. However, there is still a need to further enhance and improve their functions to progress their use in the biomedical field. A promising solution is to modify the polymer surfaces with peptides that can increase biocompatibility, cellular interactions, and receptor targeting. In recent years, peptide modifications have been used to overcome many challenges to polymer biomaterial development. This review discusses recent progress in developing peptide-modified polymers for therapeutic applications including cell-specific targeting and tissue engineering. Furthermore, we will explore some of the most frequently studied base components of these biomaterials.

Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology.

Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.

Activation probability of a single naïve T cell upon TCR ligation is controlled by T cells interacting with the same antigen-presenting cell.

Accurate recognition of antigens by specific T cells is crucial for adaptive immunity to work properly. The activation of a T-cell antigen-specific response by an antigen-presenting cell (APC) has not been clearly measured at a single T-cell level. It is also unknown whether the cell-extrinsic environment alters antigen recognition by a T cell. To measure the activation probability of a single T cell by an APC, we performed a single-cell live imaging assay and found that the activation probability changes depending not only on the antigens but also on the interactions of other T cells with the APC. We found that the specific reactivity of single naïve T cells was poor. However, their antigen-specific reactivity increased drastically when attached to an APC interacting with activated T cells. Activation of T cells was suppressed when regulatory T cells interacted with the APC. These findings suggest that although the ability of APCs to activate an antigen-specific naïve T cell is low at a single-cell level, the surrounding environment of APCs improves the specificity of the bulk response.

Rapid generation of monocyte-derived antigen-presenting cells with dendritic cell-like properties.

BACKGROUND: One of the major challenges in cellular therapy is the establishment and validation of simple and fast production protocols meeting good manufacturing practice (GMP) requirements. Dendritic cells (DCs) are of particular therapeutic interest, due to their critical role in T cell response initiation and regulation. Conventional wisdom states that DC generation from monocytes is a time-consuming protocol, taking up to 7-9 days. STUDY DESIGN AND METHODS: This study systematically screened and validated numerous culture components and conditions to identify the minimal requirements, which can give rise to functional monocyte-derived antigen-presenting cells (MoAPCs) in less than 48 h (36 h MoAPC). A total of 36 h MoAPCs were evaluated in terms of surface marker expression, endocytic capability, and induction of antigen-specific T cell expansion via flow cytometry. RESULTS: Screening of media compositions, glucose concentrations, and surface marker kinetics, particularly DC-SIGN as a DC-specific marker, allowed the generation of DC-like APCs in 36 h (36 h MoAPCs). A total of 36 h MoAPCs displayed a similar phenotype to 48 h MoAPC and standard 7 d MoDCs in terms of HLA-DP,DQ,DR, CD83, and DC-SIGN expression, while CD1a was preferentially expressed in standard MoDCs. Functional evaluation revealed that 36 h MoAPCs displayed reduced endocytosis capabilities and IL-12p70 production. However, 36 h MoAPCs were able to induce T cell expansion both in an allogenic and antigen-specific setting. CONCLUSION: Our results indicate that mature 36 h MoAPCs possess DC-like capabilities by inducing antigen-specific T cell responses. This study has important implications for the generation of DC-based cellular therapies, allowing a more cost and time-efficient generation of APCs.

Effective Activation and Expansion of Canine Lymphocytes Using a Novel Nano-Sized Magnetic Beads Approach.

Expansion protocols for human T lymphocytes using magnetic beads, which serve as artificial antigen presenting cells (aAPCs), is well-studied. Yet, the efficacy of magnetic beads for propagation and functionality of peripheral blood lymphocytes (PBLs) isolated from companion dogs still remains limited. Domestic dog models are important in immuno-oncology field. Thus, we built the platform for induction of canine PBLs function, proliferation and biological activity using nano-sized magnetic beads (termed as MicroBeads) coated with anti-canine CD3 and CD28 antibodies. Herein we reveal that activation of canine PBLs via MicroBeads induces a range of genes involved in immediate-early response to T cell activation in dogs. Furthermore, canine T lymphocytes are effectively activated by MicroBeads, as measured by cluster formation and induction of activation marker CD25 on canine T cells as quickly as 24 h post stimulation. Similar to human T cells, canine PBLs require lower activation signal strength for efficient proliferation and expansion, as revealed by titration studies using a range of MicroBeads in the culture. Additionally, the impact of temperature was assessed in multiple stimulation settings, showing that both 37°C and 38.5°C are optimal for the expansion of canine T cells. In contrast to stimulation using plant mitogen Concanavalin A (ConA), MicroBead-based activation did not increase activation-induced cell death. In turn, MicroBeads supported the propagation of T cells with an effector memory phenotype that secreted substantial IL-2 and IFN-γ. Thus, MicroBeads represent an accessible and affordable tool for conducting immunological studies on domestic dog models. Similarities in inducing intracellular signaling pathways further underscore the importance of this model in comparative medicine. Presented herein MicroBead-based expansion platforms for canine PBLs may benefit adoptive immunotherapy in dogs and facilitate the design of next-generation clinical trials in humans.

DNA origami demonstrate the unique stimulatory power of single pMHCs as T cell antigens.

T cells detect with their T cell antigen receptors (TCRs) the presence of rare agonist peptide/MHC complexes (pMHCs) on the surface of antigen-presenting cells (APCs). How extracellular ligand binding triggers intracellular signaling is poorly understood, yet spatial antigen arrangement on the APC surface has been suggested to be a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering. When targeting TCRs via stably binding monovalent antibody fragments, we found the minimum signaling unit promoting efficient T cell activation to consist of two antibody-ligated TCRs within a distance of 20 nm. In contrast, transiently engaging antigenic pMHCs stimulated T cells robustly as well-isolated entities. These results identify pairs of antibody-bound TCRs as minimal receptor entities for effective TCR triggering yet validate the exceptional stimulatory potency of single isolated pMHC molecules.

Impact of Gold Nanoparticles on the Functions of Macrophages and Dendritic Cells.

Gold nanoparticles (AuNPs) have demonstrated outstanding performance in many biomedical applications. Their safety is recognised; however, their effects on the immune system remain ill defined. Antigen-presenting cells (APCs) are immune cells specialised in sensing external stimulus and in capturing exogenous materials then delivering signals for the immune responses. We used primary macrophages (Ms) and dendritic cells (DCs) of mice as an APC model. Whereas AuNPs did not alter significantly Ms and DCs functions, the exposure to AuNPs affected differently Ms and DCs in their responses to subsequent stimulations. The secretion of inflammatory molecules like cytokines (IL-6, TNF-α), chemokine (MCP-1), and reactive oxygen species (ROS) were altered differently in Ms and DCs. Furthermore, the metabolic activity of Ms was affected with the increase of mitochondrial respiration and glycolysis, while only a minor effect was seen on DCs. Antigen presentation to T cells increased when DCs were exposed to AuNPs leading to stronger Th1, Th2, and Th17 responses. In conclusion, our data provide new insights into the complexity of the effects of AuNPs on the immune system. Although AuNPs may be considered as devoid of significant effect, they may induce discrete modifications on some functions that can differ among the immune cells.

Tumor-Targeted Nanomedicine for Immunotherapy.

Therapeutic manipulation of the immune system against cancer has revolutionized the treatment of several advanced-stage tumors. While many have benefited from these treatments, the proportion of patients responding to immunotherapies is still low. Nanomedicines have promise to revolutionize tumor treatments through spatiotemporal control of drug activity. Such control of drug function could allow enhanced therapeutic actions of immunotherapies and reduced side effects. However, only a handful of formulations have been able to reach human clinical studies so far, and even fewer systems are being used in the clinic. Among translatable formulations, self-assembled nanomedicines have shown unique and versatile features for dealing with the heterogeneity and malignancy of tumors in the clinic. Such nanomedicines can be designed to promote antitumor immune responses through a series of immunopotentiating functions after being directly injected into tumors, or achieving selective tumor accumulation upon intravenous administration. Thus, tumor-targeted nanomedicines can enhance antitumor immunity by several mechanisms, such as inducing immunogenic damage to cancer cells, altering the tumor immune microenvironment by delivering immunomodulators, or eliminating or reprogramming immunosuppressive cells, enhancing the exposure of tumor-associated antigens to antigen presenting cells, stimulating innate immunity mechanisms, and facilitating the infiltration of antitumor immune cells and their interaction with cancer cells. Moreover, nanomedicines can be engineered to sense intratumoral stimuli for activating specific immune responses or installed with ligands for increasing drug levels in tumors, granting subcellular delivery, and triggering immune signals and proliferation of immune cells. Thus, the ability of nanomedicines to exert immunomodulatory functions selectively in tumor and tumor-associated tissues, such as draining lymph nodes, increases the efficiency of the treatments, while avoiding systemic immunosuppressive toxicities and the exacerbation of adverse immune responses. Moreover, the compartmentalized structure of self-assembled nanomedicines offers the possibility to coload a variety of drugs for controlled pharmacokinetics, enhanced tumor delivery, and synergistic therapeutic output. Also, by integrating imaging functionalities into nanomedicines, it is possible to develop theranostic platforms reporting the immune settings of tumors as well as the effects of nanomedicines on the tumor immune microenvironment. Herein, we critically reviewed significant strategies for developing nanomedicines capable of potentiating antitumor immune responses by surmounting biological barriers and modulating antitumor immune signals. Moreover, the potential of these nanomedicines for developing innovative anticancer treatments by targeting particular cells is discussed. Finally, we present our perspectives on the awaiting challenges and future directions of nanomedicines in the age of immunotherapy.

Synthetic Particles for Cancer Vaccines: Connecting the Inherent Supply Chain.

Cancer vaccines have opened a new paradigm for safe and effective antitumor therapy, but they still suffer from shortcomings such as insufficient immunogenicity and immune tolerance, which seldom makes them the first choice in clinic. In fact, similar to providing a high-end product, a robust antitumor effect depends on the inherent supply chain, which attains, processes, and presents tumor-associated antigens via antigen presenting cells to T cells, which then leads to lysis of the cancer cells to release more antigens to complete the supply chain. Under these circumstances, the failure of cancer vaccines can be treated as a blockade or chain rupture. Thus, for effective tumor treatment, the key is to rationally design logistic systems to restore the supply chain.Under these circumstances, this Account summarizes our recent attempts to exploit the immunogenic trait of synthetic particles to enhance the distribution, presentation, and immune activations of the whole priming process in cancer vaccines: (1) Raw material (tumor antigen/signals) procurement: We illustrated the efforts to deliver antigens to antigen presenting cells (APCs) and draining lymph nodes for potent internalizations, and put more emphasis on the structural effect of sizes, charges, shapes, and assembly strategies for the antigen depot, lymph node transfer, and APC endocytosis. (2) Manufacture of cytotoxic T lymphocytes (CTLs) via APC recognition and presentation: We centered on exploiting the softness of two-dimensional graphene and Pickering emulsions to dynamically potentiate the immune recognition, and demonstrating the recent advances in lysosome escape strategies for enhanced antigen cross-presentations. (3) Marketing the accumulations of CTLs and the reversal of an immunosuppressive microenvironment within the tumor: We demonstrated the previous attempts to inherently cultivate the tumor tropism of the T cells via the multiantigenic repertoire and discussed the advances and challenges of combinatory cancer vaccines with an immune checkpoint blockade to reinforce the antitumor efficacy. Collectively, this Account aims to illustrate the potential of the particulate cancer vaccines to recapitalize the inherent host immune responses for the maximum antitumor effect. And by integrating the antitumor supply chain, optimized synthetic particles may shed light on the development of safe and effective particulate cancer vaccines.

Biotin Functionalized Self-Assembled Peptide Nanofiber as an Adjuvant for Immunomodulatory Response.

Biotinylated peptide amphiphile (Biotin-PA) nanofibers, are designed as a noncovalent binding location for antigens, which are adjuvants to enhance, accelerate, and prolong the immune response triggered by antigens. Presenting antigens on synthetic Biotin-PA nanofibers generated a higher immune response than the free antigens delivered with a cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN) (TLR9 agonist) adjuvant. Antigen attached Biotin-PA nanofibers trigger splenocytes to produce high levels of cytokines (IFN-γ, IL-12, TNF-α, and IL-6) and to exhibit a superior cross-presentation of the antigen. Both Biotin-PA nanofibers and CpG ODN induce a Th-1-biased IgG subclass response; however, delivering the antigen with Biotin-PA nanofibers induce significantly greater production of total IgG and subclasses of IgG compared to delivering the antigen with CpG ODN. Contrary to CpG ODN, Biotin-PA nanofibers also enhance antigen-specific splenocyte proliferation and increase the proportion of the antigen-specific CD8(+) T cells. Given their biodegradability and biocompatibility, Biotin-PA nanofibers have a significant potential in immunoengineering applications as a biomaterial for the delivery of a diverse set of antigens derived from intracellular pathogens, emerging viral diseases such as COVID-19, or cancer cells to induce humoral and cellular immune responses against the antigens.

Expression characteristics of immune factors in secondary lymphoid organs of newborn, juvenile and adult yaks (Bos grunniens).

Little is known about lymphoid organ development in yaks. In this study, we characterize and evaluate the main markers of T cell, B cell, plasma cell and antigen-presenting cell in the mesenteric lymph nodes, spleen and hemal node in newborn, juvenile and adult yaks by immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting. The structures of all organs were not fully developed in newborn. The CD3+ cells were mainly located in the paracortex area of the mesenteric lymph node and the T cell dependent area in the hemal node and spleen. CD79a+ cells were mainly detected in the lymphoid follicles. The expression of CD3 and CD79a increased from newborn to juvenile and then decreased in adults. The expression of CD3 was always higher in the spleen and CD79a was higher in the mesenteric lymph node. IgG+ and IgA+ cells were observed in all examined samples, except in newborn yak hemal node. IgG and IgA were up-regulated with age and the highest expression was observed in the mesenteric lymph node. The SIRPα and CD68 were widely expressed. A significant feature was that the SIRPα expression in the spleen was lowest in newborns but highest in juvenile and adult yaks. The expression of CD68 in the hemal node was highest in all groups and increased from newborn to adult yaks. This study sheds light on the relationship between the morphology and function of these organs and provides useful references for normal yak lymphoid organ development.

Microbiota-induced tissue signals regulate ILC3-mediated antigen presentation.

Although group 3 innate lymphoid cells (ILC3s) are efficient inducers of T cell responses in the spleen, they fail to induce CD4+ T cell proliferation in the gut. The signals regulating ILC3-T cell responses remain unknown. Here, we show that transcripts associated with MHC II antigen presentation are down-modulated in intestinal natural cytotoxicity receptor (NCR)- ILC3s. Further data implicate microbiota-induced IL-23 as a crucial signal for reversible silencing of MHC II in ILC3s, thereby reducing the capacity of ILC3s to present antigen to T cells in the intestinal mucosa. Moreover, IL-23-mediated MHC II suppression is dependent on mTORC1 and STAT3 phosphorylation in NCR- ILC3s. By contrast, splenic interferon-γ induces MHC II expression and CD4+ T cell stimulation by NCR- ILC3s. Our results thus identify biological circuits for tissue-specific regulation of ILC3-dependent T cell responses. These pathways may have implications for inducing or silencing T cell responses in human diseases.

An Experimental Study Comparing the Expansion of Peripheral Blood Natural Killer (NK) Cells Cultured with Artificial Antigen-Presenting Cells, in the Presence or Absence of Bone Marrow Mesenchymal Stem Cells (MSCs).

NK cells have been seen as potential agents in adoptive immunotherapy for cancer. The main challenge for the success of this approach is to obtain a great quantity of activated NK cells for adoptive transfer. The present study had aimed to evaluate the effect of a feeder layer of irradiated MSCs in the in vitro expansion of NK cells. MSCs were obtained from the bone marrow (BM) cells remaining in the bag and filter used in the transplantation of hematopoietic stem cells. NK cells were obtained from peripheral blood (PB) of healthy volunteers. NK expansion and activation were stimulated by culture with artificial antigen-presenting cells (aAPCs) and IL-2, in the presence or absence of BM-MSCs. NK cell proliferation, phenotypic expression and cytotoxic activity were evaluated. Both culture conditions showed high NK purity with predominance of NK CD56brightCD16+ subset post expansion. However, cultures without the presence of MSCs showed higher NK proliferation, expression of activation markers (CD16 and NKG2D) and related cytotoxic activity. In this experimental study, the presence of a feeder layer of irradiated BM-MSCs interfered negatively in the expansion of PB-NKs, limiting their growth and activation. Further investigation is needed to understand the mechanisms of NK-MSC interaction and its implications.

Mesenchymal Stromal Cells from Fetal and Maternal Placenta Possess Key Similarities and Differences: Potential Implications for Their Applications in Regenerative Medicine.

Placenta-derived mesenchymal stromal cells (MSC) have attracted more attention for their immune modulatory properties and poor immunogenicity, which makes them suitable for allogeneic transplantation. Although MSC isolated from different areas of the placenta share several features, they also present significant biological differences, which might point to distinct clinical applications. Hence, we compared cells from full term placenta distinguishing them on the basis of their origin, either maternal or fetal. We used cells developed by Pluristem LTD: PLacenta expanded mesenchymal-like adherent stromal cells (PLX), maternal-derived cells (PLX-PAD), fetal-derived cells (PLX-R18), and amniotic membrane-derived MSC (hAMSC). We compared immune modulatory properties evaluating effects on T-lymphocyte proliferation, expression of cytotoxicity markers, T-helper and T-regulatory cell polarization, and monocyte differentiation toward antigen presenting cells (APC). Furthermore, we investigated cell immunogenicity. We show that MSCs and MSC-like cells from both fetal and maternal sources present immune modulatory properties versus lymphoid (T cells) and myeloid (APC) cells, whereby fetal-derived cells (PLX-R18 and hAMSC) have a stronger capacity to modulate immune cell proliferation and differentiation. Our results emphasize the importance of understanding the cell origin and characteristics in order to obtain a desired result, such as modulation of the inflammatory response that is critical in fostering regenerative processes.

Single-cell analysis of CD8 T lymphocyte diversity during adaptive immunity.

An effective adaptive immune response to microbial infection relies on the generation of heterogeneous T lymphocyte fates and functions. CD8 T lymphocytes play a pivotal role in mediating immediate and long-term protective immune responses to intracellular pathogen infection. Systems-based analysis of the immune response to infection has begun to identify cell fate determinants and the molecular mechanisms underpinning CD8 T lymphocyte diversity at single-cell resolution. Resolving CD8 T lymphocyte heterogeneity during adaptive immunity highlights the advantages of single-cell technologies and computational approaches to better understand the ontogeny of CD8 T cellular diversity following infection. Future directions of integrating single-cell multiplex approaches capitalize on the importance of systems biology in the understanding of immune CD8 T cell differentiation and functional diversity. This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Cell Fates.