Cell Immunobiology Research Articles

Biomaterial engineering strategies for B cell immunity modulations.

B cell immunity has a penetrating effect on human health and diseases. Therapeutics aiming to modulate B cell immunity have achieved remarkable success in combating infections, autoimmunity, and malignancies. However, current treatments still face significant limitations in generating effective long-lasting therapeutic B cell responses for many conditions. As the understanding of B cell biology has deepened in recent years, clearer regulation networks for B cell differentiation and antibody production have emerged, presenting opportunities to overcome current difficulties and realize the full therapeutic potential of B cell immunity. Biomaterial platforms have been developed to leverage these emerging concepts to augment therapeutic humoral immunity by facilitating immunogenic reagent trafficking, regulating T cell responses, and modulating the immune microenvironment. Moreover, biomaterial engineering tools have also advanced our understanding of B cell biology, further expediting the development of novel therapeutics. In this review, we will introduce the general concept of B cell immunobiology and highlight key biomaterial engineering strategies in the areas including B cell targeted antigen delivery, sustained B cell antigen delivery, antigen engineering, T cell help optimization, and B cell suppression. We will also discuss our perspective on future biomaterial engineering opportunities to leverage humoral immunity for therapeutics.

Immune Imprinting and Implications for COVID-19.

Immunological memory is the key source of protective immunity against pathogens. At the current stage of the COVID-19 pandemic, heterologous combinations of exposure to viral antigens during infection and/or vaccination shape a distinctive immunological memory. Immune imprinting, the downside of memory, might limit the generation of de novo immune response against variant infection or the response to the next-generation vaccines. Here, we review mechanistic basis of immune imprinting by focusing on B cell immunobiology and discuss the extent to which immune imprinting is harmful, as well as its effect on SARS-CoV-2 infection and vaccination.

Assessing the Immune Regulatory Role of Metabolites In Vitro.

One method of immune evasion that cancer cells employ is the secretion of immune regulatory metabolites into the tumor microenvironment (TME). These metabolites can promote immunosuppressive cell subsets, while inhibiting key tumor-killing subsets, such as T cells. Thus, the identification of these metabolites may help develop methods for improving cell-based therapy. However, after identifying a potential immune regulatory metabolite, it is crucial to assess the impacts of the metabolite on T cell immunobiology. In this chapter, we describe an in vitro method of testing and analyzing the influence of a specific metabolite on T cell proliferation and function.

IMMU-20. MODULATION OF THE PERIPHERAL T CELL BIOLOGY IN GLIOBLASTOMA

Abstract Cancer is a systemic disease. Due to the exceedingly rare occurrence of metastasis of cerebral glioma, systemic alterations have, however, not been considered to play a major role in disease progression of glioma. T cells orchestrate the adaptive immune response in an antigen-specific, cytokine mediated manner. The aim of our study was to investigate how cerebral glioma impacts systemic T cell immunobiology. We performed gene expression profiling of peripheral blood T cells in patients with IDHwt glioblastomas as well as in a murine glioma model. In addition, we analyzed the levels of soluble immune biomarkers in patient blood and performed flow-cytometric phenotyping of human peripheral blood CD3+ T cells. We discovered a significant skewing of peripheral T cell phenotypes in IDHwt glioblastoma patients compared to healthy donors (HD), showing CD4+ TH1 expansion and reduced numbers of T follicular helper cells (TFH), TH1* and mucosa associated invariant T (MAIT) cells, while TH2 and TH17 percentages remained stable. Interestingly, peripheral memory CD4+ T cells exhibited reduced Fas and PD-1 expression, while CD8 T cells were primarily affected in the non-memory CD45RA+ compartment, displaying reduced numbers of CD8+ CD127+ CD27+ cells. Compared to healthy individuals, GBM patients had significantly increased levels of soluble CD27 while levels of soluble CD25 were reduced (p < 0.05). GSEA and ORA analysis of differentially expressed genes in murine gliomas showed alterations in RNA binding and processing, as well as ribosomal activity in both cell types, indicating systemic modulation in translational- and cell cycle pathways in glioblastoma. Taken together, our results demonstrate a significant skewing of the peripheral T immunobiology in patients with IDHwt gliomas. Our data highlights the importance of considering malignant glioma as a systemic disease that fundamentally alters the immune repertoire in affected patients.

Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin.

Central to the impacts of CD4 T cells, both positive in settings of infectious disease and cancer and negative in the settings of autoimmunity and allergy, is their ability to differentiate into distinct effector subsets with specialized functions. The programming required to support such responses is largely dictated by lineage-specifying transcription factors, often called 'master regulators'. However, it is increasingly clear that many aspects of CD4 T cell immunobiology that can determine the outcomes of disease states involve a broader transcriptional network. Eomesodermin (Eomes) is emerging as an important member of this class of transcription factors. While best studied in CD8 T cells and NK cells, an increasing body of work has focused on impacts of Eomes expression in CD4 T cell responses in an array of different settings. Here, we focus on the varied impacts reported in these studies that, together, indicate the potential of targeting Eomes expression in CD4 T cells as a strategy to improve a variety of clinical outcomes.

IL7RA single nucleotide polymorphisms are associated with the size and function of the MAIT cell population in treated HIV-1 infection.

MAIT cells are persistently depleted and functionally exhausted in HIV-1-infected patients despite long-term combination antiretroviral therapy (cART). IL-7 treatment supports MAIT cell reconstitution in vivo HIV-1-infected individuals and rescues their functionality in vitro. Single-nucleotide polymorphisms (SNPs) of the IL-7RA gene modulate the levels of soluble(s)IL-7Rα (sCD127) levels and influence bioavailability of circulating IL-7. Here we evaluate the potential influence of IL-7RA polymorphisms on MAIT cell numbers and function in healthy control (HC) subjects and HIV-1-infected individuals on long-term cART. Our findings indicate that IL-7RA haplotype2 (H2*T), defined as T-allele carriers at the tagging SNP rs6897932, affects the size of the peripheral blood MAIT cell pool, as well as their production of cytokines and cytolytic effector proteins in response to bacterial stimulation. H2*T carriers had lower sIL-7Rα levels and higher MAIT cell frequency with enhanced functionality linked to higher expression of MAIT cell-associated transcription factors. Despite an average of 7 years on suppressive cART, MAIT cell levels and function in HIV-1-infected individuals were still significantly lower than those of HC. Notably, we observed a significant correlation between MAIT cell levels and cART duration only in HIV-1-infected individuals carrying IL-7RA haplotype 2. Interestingly, treatment with sIL-7Rα in vitro suppressed IL-7-dependent MAIT cell proliferation and function following cognate stimulations. These observations suggest that sIL-7Rα levels may influence MAIT cell numbers and function in vivo by limiting IL-7 bioavailability to MAIT cells. Collectively, these observations suggest that IL-7RA polymorphisms may play a significant role in MAIT cell biology and influence MAIT cells recovery in HIV-1 infection. The potential links between IL7RA polymorphisms, MAIT cell immunobiology, and HIV-1 infection warrant further studies going forward.

B-Cell-Directed Therapies: A New Era in Multiple Sclerosis Treatment.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) that often progresses to severe disability. Previous studies have highlighted the role of T cells in disease pathophysiology; however, the success of B-cell-targeted therapies has led to an increased interest in how B cells contribute to disease immunopathology. In this review, we summarize evidence of B-cell involvement in MS disease mechanisms, starting with pathology and moving on to review aspects of B cell immunobiology potentially relevant to MS. We describe current theories of critical B cell contributions to the inflammatory CNS milieu in MS, namely (i) production of autoantibodies, (ii) antigen presentation, (iii) production of proinflammatory cytokines (bystander activation), and (iv) EBV involvement. In the second part of the review, we summarize medications that have targeted B cells in patients with MS and their current position in the therapeutic armamentarium based on clinical trials and real-world data. Covered therapeutic strategies include the targeting of surface molecules such as CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) and CD19 (inebilizumab), and molecules necessary for B-cell activation such as B cell activating factor (BAFF) (belimumab) and Bruton's Tyrosine Kinase (BTK) (evobrutinib). We finally discuss the use of B-cell-targeted therapeutics in pregnancy.

Transcriptional profiling of human Vδ1 Tcells reveals a pathogen-driven adaptive differentiation program.

SUMMARYγδ T cells are generally considered innate-like lymphocytes, however, an ‘‘adaptive-like’’ γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1+ T cells segregate into TCF7+LEF1+Granzyme Bneg (Tnaive) or T-bet+Eomes+ BLIMP-1+Granzyme B+ (Teffector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in Teffector cells. Transcriptional reprogramming mirrors changes within CD8+ αβ T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1+ and CD8+ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from Tnaive to Teffector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9+Vδ2+ T cells exhibit a distinct ‘‘innate-effector’’ transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8+ T cells.

Exploring the functionality of CD56+ MAIT cell populations across human tissues

Abstract Mucosa-associated invariant T (MAIT) cells are an evolutionarily conserved population of T cells serving a sentinel function at mucosal barrier sites to mediate immune protection. MAIT cells utilize their semi-invariant T cell receptor (TCR) to react to non-peptidic antigens derived from microbial riboflavin metabolites, presented on monomorphic MHC-class I-like MR1 molecules. In addition to TCR-dependent recognition of vitamin B2metabolites, MAIT cells sense and respond to local inflammatory cytokines in an innate-like manner. Surface expression of CD56 was previously shown to be associated with enhanced MAIT cell sensitivity to TCR-independent activation. However, the regulation, frequency, or relevance of CD56 expression on human MAIT cells is currently not well understood. Flow cytometry revealed heterogeneity of CD56 expression across donor-matched tissues obtained from human organ donors. Strikingly, the majority of liver MAIT cells expressed CD56, whereas expression was consistently lower in other tissues. We evaluated de novo CD56 expression on blood-derived sorted CD56-negative MAIT cells following IL-7 or antigen exposure which is likely to occur in the hepatic acute phase response. CD56-negative MAIT cells strongly upregulated CD56 expression after IL-7 stimulation and maintained CD56 expression for up to 19 days. Exposure to MR1-presented antigen induced CD56 expression similarly but required prior cell proliferation. In summary, we identify heterogeneity between MAIT cell populations of different tissue origin and determine the dynamic regulation of the CD56-associated innate-like characteristics to shed light on unknown aspects of MAIT cell diversity and immunobiology.

1009P Current strategies of cell and gene therapy for solid tumors: Preliminary results of the joint international ESMO and EBMT Cell Therapy and Immunobiology Working Party questionnaire-based survey

Among novel strategies for treatment of solid tumors (ST), cell and/or gene therapy (CT/GT) products are increasingly under investigation, also based on encouraging results observed in lymphoid cancers with industry-manufactured CAR-T-cells. Available information on ongoing studies in ST is limited, due to the variety of programs and infrastructures involved in advanced therapy medicinal products (ATMPs) manufacturing and delivery.

Hunting for better biomarkers of response: where is real progress being made in understanding why patients do and don’t respond to I-O therapeutics?

Adil DaudProfessor of Medicine and Dermatology, University of California; and Director of the Melanoma program, Helen Diller Family Cancer Center, UCSFDr Adil Daud is an expert in immunotherapy and has pioneered the development of novel immunotherapeutics and targeted therapies. His fellowship in medical oncology was at the Memorial Sloan Kettering Cancer Center and was a faculty member at the Moffitt Cancer Center in Tampa, Fl. He is currently Professor of Medicine and Dermatology at the University of California, San Francisco. He is the director of the Melanoma Program and melanoma clinical research at the Helen Diller Family Cancer Center at UCSF. He led the development of IL-12 in melanoma and has developed novel technology to deliver it in vivo. He has played a major role in developing PD-1 antibodies in cancer therapy. Recently he has developed novel assays to determine immune responsiveness in vivo. These assays can determine the likelihood of response to immune therapy and provide novel insights into immune drug development. He has collaborated on numerous clinical and translational clinical trials that have yielded insights into the use of immunotherapy.Steven FlingSenior Staff Scientist, Fred Hutchinson Cancer Research Center; and Lab Director, Central Immune Monitoring LabSteven Fling, PhD serves as Lab Director for Central Immune Monitoring Lab (CIML), overseeing correlative biomarker studies for the NCI funded CITN (Cancer Immunotherapy Trials Network) and the industry funded ION (Immune Oncology Network). CITN/ION conducts early-stage, multicenter IO clinical trials, with a focus on agents/combinations to potentiate effective immune responses. Dr. Fling has >24 years research experience in T cell immunobiology, cancer vaccine and immunotherapeutic discovery, including ~13 years managing immunology research labs and directorship of collaborative research networks and consortia. Previously Dr. Fling served as Project Director for the IAVI’s Neutralizing Antibody Consortium, an international consortium working to develop a vaccine for HIV and in 2009 established lab operations at IAVI’s Neutralizing Antibody Center at the Scripps Research Institute (La Jolla, CA). In biotech R&D, Dr. Fling worked on vaccines for cancer and infectious diseases including adjuvant development at Corixa Corp (Seattle, WA) and as an Investigator in the Adjuvant Group for GSK Biologicals.John RossiSenior Director, Department of Translational Medicine, KiteI joined Kite in 2015 after 13 years at Amgen. I am currently a Senior Director in the Department of Translational Medicine at Kite and lead all pharmacology activities related to the clinical development of Kite’s cell therapy pipeline. At Kite, I have built an effective translational team to support the clinical development of axicabtagene ciloleucel (Yescarta®) and KTE-X19 (Tecartus®). My team has contributed directly to the regulatory approval of these products through pharmacokinetic and pharmacodynamic evaluation. Among many achievements at Kite, I have represented the organization through external scientific presentations and collaborative manuscripts with leading academic researchers such as Steven Rosenberg and James Kochenderfer at the NCI. Accomplishments include the discovery of metrics to characterize CAR T based on functionality, novel biomarker knowledge of how CARs work in the clinic, mechanistic information on toxicities and insights into the biology of the TME, including immune checkpoints, and the role of IL-15 in the context of CAR T-cell function.Majid GhoddusiSenior Director, Clinical Biomarkers, Poseida TherapeuticsDr Ghoddusi has over 15 years of experience in some of the most challenging areas of oncology with focus on drug discovery and clinical development. Dr Ghoddusi has broad and overarching insights into unmet therapeutic areas with expertise in translational sciences and clinical biomarker development which allows him to provide unique perspective on how to propel therapeutic projects from discovery to approval. Trained as a translational pathologist he has held numerous positions at large pharmaceutical and small biotech companies including Novartis, Celgene and Juno Therapeutics. His current focus at Poseida Therapeutic is Gene and Cellular Therapy.

Hunting for better biomarkers of response: where is real progress being made in understanding why patients do and don’t respond to I-O therapeutics?

Adil DaudProfessor of Medicine and Dermatology, University of California; and Director of the Melanoma program, Helen Diller Family Cancer Center, UCSFDr Adil Daud is an expert in immunotherapy and has pioneered the development of novel immunotherapeutics and targeted therapies. His fellowship in medical oncology was at the Memorial Sloan Kettering Cancer Center and was a faculty member at the Moffitt Cancer Center in Tampa, Fl. He is currently Professor of Medicine and Dermatology at the University of California, San Francisco. He is the director of the Melanoma Program and melanoma clinical research at the Helen Diller Family Cancer Center at UCSF. He led the development of IL-12 in melanoma and has developed novel technology to deliver it in vivo. He has played a major role in developing PD-1 antibodies in cancer therapy. Recently he has developed novel assays to determine immune responsiveness in vivo. These assays can determine the likelihood of response to immune therapy and provide novel insights into immune drug development. He has collaborated on numerous clinical and translational clinical trials that have yielded insights into the use of immunotherapy.Steven FlingSenior Staff Scientist, Fred Hutchinson Cancer Research Center; and Lab Director, Central Immune Monitoring LabSteven Fling, PhD serves as Lab Director for Central Immune Monitoring Lab (CIML), overseeing correlative biomarker studies for the NCI funded CITN (Cancer Immunotherapy Trials Network) and the industry funded ION (Immune Oncology Network). CITN/ION conducts early-stage, multicenter IO clinical trials, with a focus on agents/combinations to potentiate effective immune responses. Dr. Fling has >24 years research experience in T cell immunobiology, cancer vaccine and immunotherapeutic discovery, including ~13 years managing immunology research labs and directorship of collaborative research networks and consortia. Previously Dr. Fling served as Project Director for the IAVI’s Neutralizing Antibody Consortium, an international consortium working to develop a vaccine for HIV and in 2009 established lab operations at IAVI’s Neutralizing Antibody Center at the Scripps Research Institute (La Jolla, CA). In biotech R&D, Dr. Fling worked on vaccines for cancer and infectious diseases including adjuvant development at Corixa Corp (Seattle, WA) and as an Investigator in the Adjuvant Group for GSK Biologicals.John RossiSenior Director, Department of Translational Medicine, KiteI joined Kite in 2015 after 13 years at Amgen. I am currently a Senior Director in the Department of Translational Medicine at Kite and lead all pharmacology activities related to the clinical development of Kite’s cell therapy pipeline. At Kite, I have built an effective translational team to support the clinical development of axicabtagene ciloleucel (Yescarta®) and KTE-X19 (Tecartus®). My team has contributed directly to the regulatory approval of these products through pharmacokinetic and pharmacodynamic evaluation. Among many achievements at Kite, I have represented the organization through external scientific presentations and collaborative manuscripts with leading academic researchers such as Steven Rosenberg and James Kochenderfer at the NCI. Accomplishments include the discovery of metrics to characterize CAR T based on functionality, novel biomarker knowledge of how CARs work in the clinic, mechanistic information on toxicities and insights into the biology of the TME, including immune checkpoints, and the role of IL-15 in the context of CAR T-cell function.Majid GhoddusiSenior Director, Clinical Biomarkers, Poseida TherapeuticsDr Ghoddusi has over 15 years of experience in some of the most challenging areas of oncology with focus on drug discovery and clinical development. Dr Ghoddusi has broad and overarching insights into unmet therapeutic areas with expertise in translational sciences and clinical biomarker development which allows him to provide unique perspective on how to propel therapeutic projects from discovery to approval. Trained as a translational pathologist he has held numerous positions at large pharmaceutical and small biotech companies including Novartis, Celgene and Juno Therapeutics. His current focus at Poseida Therapeutic is Gene and Cellular Therapy.

The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes.

T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

Lymphoid stromal cells-more than just a highway to humoral immunity.

The generation of high-affinity long-lived antibody responses is dependent on the differentiation of plasma cells and memory B cells, which are themselves the product of the germinal centre (GC) response. The GC forms in secondary lymphoid organs in response to antigenic stimulation and is dependent on the coordinated interactions between many types of leucocytes. These leucocytes are brought together on an interconnected network of specialized lymphoid stromal cells, which provide physical and chemical guidance to immune cells that are essential for the GC response. In this review we will highlight recent advancements in lymphoid stromal cell immunobiology and their role in regulating the GC, and discuss the contribution of lymphoid stromal cells to age-associated immunosenescence.

MAIT Cell Loss and Reconstitution in HIV-1 Disease.

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin-related metabolites presented by the evolutionarily conserved MHC class I-related (MR1) molecule. MAIT cells are abundant in circulation and mucosal tissues and are poised to mount rapid effector responses against diverse microbial organisms. Despite the absence of virally encoded riboflavin-related metabolite antigens, MAIT cells can respond to viral infections in an MR1-independent and cytokine-dependent manner. In chronic HIV-1 infection, MAIT cells are persistently depleted and functionally exhausted. Long-term effective combination antiretroviral therapy can only partially rescue MAIT cell numbers and dysfunction. Our understanding of the mechanisms underlying MAIT cell loss in HIV-1 infection is still incomplete, and to date, few effective strategies to recover their loss in humans are available. Here, we review current knowledge concerning the mechanisms of MAIT cell responses and loss in different stages of HIV-1 infection and how we may potentially develop strategies to restore these cells in the clinical setting. We further discuss novel strategies that may aid future investigations into MAIT cell immunobiology in HIV-1 infection, including the potential use of three-dimensional organoid models to dissect the mechanisms of MAIT cell depletion and to explore interventions that may restore their numbers and functionality.

T cell immunobiology and cytokine storm of COVID-19.

2019 coronavirus disease (COVID‐19) presents as a newly recognized pneumonia and could rapidly progress into acute respiratory distress syndrome which has brought about a global pandemic. Until now, no curative therapy has been strongly recommended for COVID‐19 except for personalized supportive care. T cells and virus‐specific T cells are essential to protect against virus infection, including COVID‐19. Delayed immune reconstitution (IR) and cytokine storm (CS) remain serious obstacles for the cure of COVID‐19. Most COVID‐19 patients, especially among elderly patients, had marked lymphopenia and increased neutrophils, but T cell counts in severe COVID‐19 patients surviving the disease gradually restored later. Elevated pro‐inflammatory cytokines, particularly IL‐6, IL‐10, IL‐2 and IL‐17, and exhausted T cells are found in peripheral blood and the lungs. It suggests that Thymosin α1 and adoptive COVID‐19‐specific T cells could improve IR, while convalescent plasma, IL‐6 blockade, mesenchymal stem cells and corticosteroids could suppress CS. More clinical studies in this field worldwide are urgently warranted to pave the way for therapy of COVID‐19 in the future.

The B cell immunobiology that underlies CNS autoantibody-mediated diseases.

A rapidly expanding and clinically distinct group of CNS diseases are caused by pathogenic autoantibodies that target neuroglial surface proteins. Despite immunotherapy, patients with these neuroglial surface autoantibody (NSAb)-mediated diseases often experience clinical relapse, high rates of long-term morbidity and adverse effects from the available medications. Fundamentally, the autoantigen-specific B cell lineage leads to production of the pathogenic autoantibodies. These autoantigen-specific B cells have been consistently identified in the circulation of patients with NSAb-mediated diseases, accompanied by high serum levels of autoantigen-specific antibodies. Early evidence suggests that these cells evade well-characterized B cell tolerance checkpoints. Nearer to the site of pathology, cerebrospinal fluid from patients with NSAb-mediated diseases contains high levels of autoantigen-specific B cells that are likely to account for the intrathecal synthesis of these autoantibodies. The characteristics of their immunoglobulin genes offer insights into the underlying immunobiology. In this Review, we summarize the emerging knowledge of B cells across the NSAb-mediated diseases. We review the evidence for the relative contributions of germinal centres and long-lived plasma cells as sources of autoantibodies, discuss data that indicate migration of B cells into the CNS and summarize insights into the underlying B cell pathogenesis that are provided by therapeutic effects.

Single Cell RNA Sequencing of Human Liver Infiltrating B Cells in Primary Biliary Cholangitis (PBC)

Abstract Increasing evidence supports the concept that dysregulated B cell differentiation and activation are pivotal in the initiation and progression of autoimmune disorders, in both antibody (Ab)-dependent and Ab-independent mechanisms. Antimitochondrial antibodies (AMA), the serologic hallmark of PBC, are present in greater than 95% of patients with PBC, with a long latency period between the detection of autoantibodies and the onset of clinical disease. However, the mechanisms involved in the role of B cells in the pathogenesis of PBC have remained enigmatic. Herein, we have applied scRNA sequencing to simultaneously characterize B cell repertoire and transcriptome status in blood-liver paired samples from patients with PBC. Our data reveal that there is a dramatic increase in the heterogeneity of the blood CD27− B-cell population in PBC as compared to control. Strikingly, this overwhelmingly expanded naïve-like population were IgM+/IgD+, and encoded by germline sequences. In contrast with blood B cells, the dominant liver CD27− B-cell population is comprised of a high frequency of class-switched clonal B cells, which strongly express MHC class II genes. Upon stimulation with CpG (a surrogate TI-antigen), PBC CD27− B-cell populations markedly expanded and were accompanied by a significantly reduced expression of MARCKS, a newly identified molecule that suppresses active BCR signaling, as compared to healthy controls. Our data indicate that PBC CD27− B-cells exhibit abnormalities and heterogeneity, which may arise from a consistent exposure to TI-antigens. Our findings underscore the significance of B cells in PBC and suggest that more efforts should be placed on PBC B cell immunobiology and as potential therapeutic targets.

Regulatory T cells in solid organ transplantation.

The induction of graft tolerance remains the holy grail of transplantation. This is important as chronic allograft dysfunction and the side effects of immunosuppression regimens place a major burden on the lives of transplant patients and their healthcare systems. This has mandated the need to understand the immunobiology of graft rejection and identify novel therapeutics. Regulatory T (Treg) cells play an important role in modulating pro‐inflammatory microenvironments and maintaining tissue homeostasis. However, there are fundamental unanswered questions regarding Treg cell immunobiology. These cells are a heterogeneous entity with functionally diverse roles. Moreover, the adoption of novel deeper immunophenotyping and genomic sequencing technologies has identified this phenotype and function to be more complex than expected. Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. From a clinical perspective, the recent decade has seen different clinical teams commence and complete first‐in‐man clinical trials utilising Treg cells as an adoptive cellular therapy. In this review, we discuss these trials from a translational perspective with an important focus on safety. Finally, we identify crucial knowledge gaps for future study.

The impact of endoplasmic reticulum stress responses in dendritic cell immunobiology.

Dendritic cells (DCs) are critical for bridging innate and adaptive immunity. They do so by presenting antigens to T cells, and by expressing diverse molecules that further promote T cell activation, differentiation and memory formation. During this process, intracellular and extracellular factors can perturb the protein-folding capacity of endoplasmic reticulum (ER) and induce a cellular state of "ER stress," which is controlled and resolved by the unfolded protein response (UPR). Interestingly, various studies have shown that DCs can activate UPR-related pathways even in the absence of global ER stress, and that this process can modulate their normal activity. In other settings, such as cancer, adverse microenvironmental conditions have been demonstrated to evoke severe ER stress and persistent activation of the UPR in tumor-infiltrating DCs. This process disrupts their metabolism and local antigen-presenting capacity, hence impeding the initiation and maintenance of anti-cancer immunity. Here, we review recent findings on how canonical and non-canonical UPR activation impacts DC immunobiology at the steady-state, upon activation via pattern recognition receptors, and under diverse pathological conditions. We also discuss the potential therapeutic implications that targeting the UPR in DCs may have in the context of cancer and in other pathologies such as graft-versus-host disease.