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The incomplete removal of T cells that are reactive against self-proteins during their differentiation in the thymus requires mechanisms of tolerance that prevent their effector function within the periphery. A further challenge is imposed by the need to establish tolerance to the holobiont self, which comprises a highly complex community of commensal microorganisms. Here, we review recent advances in the investigation of peripheral T cell tolerance, focusing on new insights into mechanisms of tolerance to the gut microbiota, including tolerogenic antigen-presenting cell types and immunomodulatory lymphocytes, and their layered ontogeny that underlies developmental windows for establishing intestinal tolerance. While emphasizing the intestine as a model tissue for studying peripheral T cell tolerance, we highlight overlapping and distinct pathways that underlie tolerance to self-antigens versus commensal antigens within a broader framework for immune tolerance.

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

Regulatory T cells (Tregs) promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses. Under certain inflammatory conditions, Tregs can lose their lineage stability and function. Previous studies have reported that ex vivo exposure to retinoic acid (RA) enhances Treg function and stability. However, it is unknown how RA receptor signaling in Tregs influences these processes in vivo. Herein, we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor (DN) RARα in all T cells. Despite the fact that DNRARα conventional T cells are hypofunctional, Tregs had increased CD25 expression, STAT5 pathway activation, mTORC1 signaling and supersuppressor function. Furthermore, DNRARα Tregs had increased inhibitory molecule expression, amino acid transporter expression, and metabolic fitness and decreased antiapoptotic proteins. Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist. Unexpectedly, Treg-specific expression of DNRARα resulted in distinct phenotypes, such that a single allele of DNRARα in Tregs heightened their suppressive function, and biallelic expression led to loss of suppression and autoimmunity. The loss of Treg function was not cell intrinsic, as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARα and wild-type bone marrow maintained the enhanced suppressive capacity. Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling. Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct cell states. Here we present single-cell aggregation of cell states (SEACells), an algorithm for identifying metacells that overcome the sparsity of single-cell data while retaining heterogeneity obscured by traditional cell clustering. SEACells outperforms existing algorithms in identifying comprehensive, compact and well-separated metacells in both RNA and assay for transposase-accessible chromatin (ATAC) modalities across datasets with discrete cell types and continuous trajectories. We demonstrate the use of SEACells to improve gene–peak associations, compute ATAC gene scores and infer the activities of critical regulators during differentiation. Metacell-level analysis scales to large datasets and is particularly well suited for patient cohorts, where per-patient aggregation provides more robust units for data integration. We use our metacells to reveal expression dynamics and gradual reconfiguration of the chromatin landscape during hematopoietic differentiation and to uniquely identify CD4 T cell differentiation and activation states associated with disease onset and severity in a Coronavirus Disease 2019 (COVID-19) patient cohort.

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4 T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3 T cells into peripheral Foxp3 Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic. Key Points: • A novel RXR agonist attenuates acute GVHD, while retaining graft-versus-leukemia responses. • The RXR agonist enhances Treg generation and stabilizes Foxp3, even in a highly inflammatory environment.

Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct cell states. Here, we present single-cell aggregation of cell-states (SEACells), an algorithm for identifying metacells; overcoming the sparsity of single-cell data, while retaining heterogeneity obscured by traditional cell clustering. SEACells outperforms existing algorithms in identifying accurate, compact, and well-separated metacells in both RNA and ATAC modalities across datasets with discrete cell types and continuous trajectories. We demonstrate the use of SEACells to improve gene-peak associations, compute ATAC gene scores and measure gene accessibility in each metacell. Metacell-level analysis scales to large datasets and are particularly well suited for patient cohorts, including facilitation of data integration. We use our metacells to reveal expression dynamics and gradual reconfiguration of the chromatin landscape during hematopoietic differentiation, and to uniquely identify CD4 T cell differentiation and activation states associated with disease onset and severity in a COVID-19 patient cohort.

Foxp3(+) T regulatory (Treg) cells promote immunological tumor tolerance, but how their immune-suppressive function is regulated in the tumor microenvironment (TME) remains unknown. Here, we used intravital microscopy to characterize the cellular interactions that provide tumor-infiltrating Treg cells with critical activation signals. We found that the polyclonal Treg cell repertoire is pre-enriched to recognize antigens presented by tumor-associated conventional dendritic cells (cDCs). Unstable cDC contacts sufficed to sustain Treg cell function, whereas T helper cells were activated during stable interactions. Contact instability resulted from CTLA-4-dependent downregulation of co-stimulatory B7-family proteins on cDCs, mediated by Treg cells themselves. CTLA-4-blockade triggered CD28-dependent Treg cell hyper-proliferation in the TME, and concomitant Treg cell inactivation was required to achieve tumor rejection. Therefore, Treg cells self-regulate through a CTLA-4- and CD28-dependent feedback loop that adjusts their population size to the amount of local co-stimulation. Its disruption through CTLA-4-blockade may off-set therapeutic benefits in cancer patients.

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes based on their dynamic co-localization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GC) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of T(H)1 cells at the T-B boundary. The encounter of B and T(H)1 cells at the T-B boundary enables IFNγ produced by the latter to induce IgG2c class switching. Within GCs, T-bet(+) T(FH) cells represent a specialized stable sub-lineage required for GC growth, but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T

Funder: Kennedy Trust studentship, Funder: Oxford-UCB Prize Fellowship, Funder: National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University and Versus Arthritis Research into Inflammatory Arthritis Centre; ref. 22072)., Funder: NIHR Birmingham BRC at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, Funder: St Baldrick’s Foundation, Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. We used three complementary single cell approaches to study leukocytes from PsA joints. Mass cytometry (CyTOF) demonstrated marked (>3 fold) expansion of memory CD8 T cells in the joints compared to matched blood. Further exploration of the memory CD8 compartment using both droplet and plate based single cell RNA sequencing of paired alpha and beta chain T cell receptor sequences identified pronounced CD8 T cell clonal expansions within the joints, strongly suggesting antigen driven expansion. These clonotypes exhibited distinct gene expression profiles including cycling, activation, tissue homing and tissue residency markers. Pseudotime analysis of these clonal CD8 populations identified trajectories in which tissue residency can represent an intermediate developmental state giving rise to activated, cycling and exhausted CD8 populations. Comparing T-cell clonality across patients further revealed specificity convergence of clones against a putative common antigen. We identify chemokine receptor CXCR3 as upregulated in expanded synovial clones, and elevation of two CXCR3 ligands, CXCL9 and CXCL10, in PsA synovial fluid.

Inhibitory signaling on T cells maintains “naïvety” to self-antigen

Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells1. Activated T cells play a role in disease2 but the cell types that drive the recruitment and activation of immune cells within the synovium are not known. Here, we utilised droplet-based and full length single cell mRNA sequencing to obtain a quantitative map of the cellular landscape of JIA. We studied 45,715 cells from the synovial fluid of inflamed knee joints and peripheral blood. We identified a population of synovial innate lymphoid cells (ILCs), shared across patients, that exhibited a unique transcriptional profile in comparison to canonical ILC subtypes. Validation at protein-level across a spectrum of autoimmune arthritides revealed that these ILCs are pathologically expanded in a particular type of JIA. Using statistical tools to assess cellular interactions in synovial fluid, ILCs emerged as a central node of communication, expressing the full repertoire of genes required to orchestrate and maintain the inflammatory milieu. Several ILC-mediated signalling pathways may lend themselves as novel therapeutic targets. Together our findings demonstrate a distinct ILC subtype associated with a tissue-specific childhood autoimmune disease.

The importance of vitamin A for host defense is undeniable and the study of its mechanisms is paramount. Of the estimated 250 million preschool children who are vitamin A-deficient (VAD), 10% will die from their increased susceptibility to infectious disease. Vitamin A supplementation was established in the 1980s as one of the most successful interventions in the developing world. Understanding how vitamin A controls immunity will help curb the mortality and morbidity associated with vitamin A deficiency and exploit the immune-enhancing capacity of vitamin A to heighten host resistance to infectious disease. The discoveries that retinoic acid (RA) imprints the homing of leukocytes to the gut and enhances the induction of regulatory T cells, highlighted a potential role for RA in mucosal tolerance. However, more recently emerging data tell of a more profound systemic impact of RA on leukocyte function and commitment. In animal models using genetic manipulation of RA signaling, we learned when and how RA controls T cell fate. Here, we review the role for RA as a critical checkpoint regulator in the differentiation of CD4(+) T cells within the immune system.

Intimal vascular lesions are considered features of acute T-cell-mediated rejection yet can occur in the absence of tubulointerstitial inflammation, termed isolated 'v' lesions. The clinical significance of these lesions is unclear. The diagnosis requires a biopsy with the presence of arteries. The frequency of adequate biopsies was analysed in 89 renal transplant biopsies from 57 paediatric renal allograft recipients, and the incidence of isolated endarteritis was determined. 60 (67%) biopsies contained an artery and of these, isolated 'v' lesions occurred in 6 (10%). 5 (83%) biopsies with isolated 'v' lesions were associated with positive DSA, suggesting that these lesions may represent acute antibody-mediated rejection. Patients with vessel-negative biopsies had an increased decline in eGFR (median -20.5, IQR -24.4 to 1.2 ml/min/1.73 m(2) vs. -9.6, IQR -78.7 to -6.8 ml/min/1.73 m(2) ; P = 0.01). Patients with vessel-negative biopsies were more likely to have repeat biopsy for ongoing allograft dysfunction, (25.0% vs. 2.4%; P < 0.01). The data suggest that isolated 'v' lesions are more common than previously thought. A significant proportion of biopsies classified as 'normal' or 'borderline change' in the absence of a large vessel may represent undiagnosed acute rejection. This may result in suboptimal therapy with possible adverse effects on renal outcome.

Summary Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer., Graphical Abstract, Highlights • Single-cell analyses reveal novel dendritic cell subsets • Major cDC2 subsets differentially express T-bet and RORγt • Distinct pro- and anti-inflammatory potential of T-bet+ and Tbet– cDC2s • Transcriptional basis for cDC2 heterogeneity conserved across mouse and human, Single-cell analyses of dendritic cells reveals new subsets with distinct pro- and anti-inflammatory potential.

Background CD4 T cells with features of both T-helper-type 1 (Th1) and 17 (Th17) cells have been implicated in several autoimmune diseases suggesting that plasticity among CD4 T-cell lineages is potentially pathogenic. However, the factors that regulate T-cell lineage stability are largely unknown. Retinoic acid (RA) is synthesised at sites of inflammation. We hypothesised that retinoic acid, a profound epigenetic modifier, could regulate T-cell lineage stability. Methods We used a mouse model in which retinoic acid signalling is specifically ablated within the T-cell compartment through overexpression of a dominant negative retinoic acid receptor α (RARα) (dnRARα mice) to investigate its role in the regulation of Th1 lineage stability. Genome-wide ChIP-seq analysis was done to identify RARα targets. In parallel, we performed global mapping of regulatory regions, termed enhancers, to gain mechanistic insight into retinoic acid regulation of T-cell fate. The in-vivo relevance of our findings was determined in a model of oral antigen-induced intestinal inflammation. Findings We found that retinoic acid is crucial for maintenance of the Th1 lineage. Abrogation of retinoic acid signalling in Th1 cells resulted in loss of T-bet expression and STAT4 activity. Th1 cells from dnRARα mice showed enhanced plasticity with the emergence of hybrid Th1–Th17 and Th17 effector cells. Global analysis of RARα binding and enhancer mapping revealed that RA–RARα directly regulated enhancer activity at Th1 lineage defining genes while repressing genes that regulate Th17 cell fate. Retinoic acid inhibition of Th1 plasticity was essential for maintaining appropriate Th cell responses in vivo and preventing autoimmune intestinal inflammation. Interpretation Our study has identified RA–RARα as a key component of the regulatory network governing maintenance and plasticity of Th1 cells and defines a new pathway for the development of pathogenic Th17 cells. Retinoids might be novel therapeutic agents for Th17-associated autoimmune diseases. Funding Wellcome Trust.

Although vitamin A was recognized as an “anti-infective vitamin” over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.

Summary Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes. We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10–20% directly alter recognizable transcription factor binding motifs. Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

The importance of vitamin A for host defense is undeniable and the study of its mechanisms is paramount. Of the estimated 250 million preschool children who are vitamin A-deficient (VAD), 10% will die from their increased susceptibility to infectious disease. Vitamin A supplementation was established in the 1980s as one of the most successful interventions in the developing world. Understanding how vitamin A controls immunity will help curb the mortality and morbidity associated with vitamin A deficiency and exploit the immune-enhancing capacity of vitamin A to heighten host resistance to infectious disease. The discoveries that retinoic acid (RA) imprints the homing of leukocytes to the gut and enhances the induction of regulatory T cells, highlighted a potential role for RA in mucosal tolerance. However, more recently emerging data tell of a more profound systemic impact of RA on leukocyte function and commitment. In animal models using genetic manipulation of RA signaling, we learned when and how RA controls T cell fate. Here, we review the role for RA as a critical checkpoint regulator in the differentiation of CD4(+) T cells within the immune system.

Vitamin A deficiency leads to increased susceptibility to a spectrum of infectious diseases. The studies presented dissect the intrinsic role of each of the retinoic acid receptor (RAR) isoforms in the clonal expansion, differentiation, and survival of pathogen-specific CD8 T cells in vivo. The data show that RARα is required for the expression of gut-homing receptors on CD8+ T cells and survival of CD8+ T cells in vitro. Furthermore, RARα is essential for survival of CD8+ T cells in vivo following Listeria monocytogenes infection. In contrast, RARβ deletion leads to modest deficiency in Ag-specific CD8+ T cell expansion during infection. The defective survival of RARα-deficient CD8+ T cells leads to a deficiency in control of L. monocytogenes expansion in the spleen. To our knowledge, these are the first comparative studies of the role of RAR isoforms in CD8+ T cell immunity.

A career path in academic paediatric medicine is an extremely rewarding one, and while not traditionally considered an academic specialty, it offers a wealth of exciting research opportunities. Developing academic paediatrics is becoming increasingly important, as recently reviewed in the Royal College of Paediatrics and Child Health (RCPCH) Turning the Tide report, and developing future leaders in academic paediatrics is a key goal of the academic training pathways. Strategies are being implemented to ensure that the enthusiasm of academic trainees is maintained, and their development into future leaders is secured.

Retinoic acid (RA), a metabolite of vitamin A, modulates a variety of aspects of the immune system, primarily because of its diverse effects on a wide range of immune cells. Initiation of RA-mediated transcription requires the binding of RA to heterodimeric nuclear receptors composed of RA receptors (RARα, β, and γ) and retinoid X receptors (RXRα, β, and γ). Although RA signaling is tolerogenic under steady state conditions, previous studies, including ours, have shown that RA can enhance pro-inflammatory responses in acute graft-versus-host disease (aGVHD) (Blood. 2013; 122(12): 2125). In that study, we demonstrated that donor T cells expressing a dominant negative RARα (DNRARα) markedly impaired GVHD lethality capacity. This paradoxical function in aGVHD was attributed to excessive RA production caused by the upregulation of RA-synthesizing enzymes, retinaldehyde dehydrogenases (RALDH), in hematopoietic and non-hematopoietic cells. In the current study, we investigated genetic and translational approaches to ablate RA synthesis and signaling as a means to treat aGVHD. The 4 isoforms of the RALDH enzyme are differentially expressed in a variety of cell types. RALDH-2 is the predominant isoform in dendritic cells (DCs), whereas RALDH-1 levels were found to be higher in intestinal epithelial cells (IECs) during aGVHD. We hypothesized that conditional deletion of either RALDH-2 in host CD11c+ DCs, or RALDH-1 in host IECs using a Cre-Lox system would diminish RA synthesis and reduce aGVHD. Consistent with this hypothesis, ablation of RA synthesis by RALDH-2 in host CD11c+ DCs significantly reduced aGVHD (Figure 1A; p We further explored RA signaling in aGVHD using a translational approach. IRX4204 is a novel and highly specific RXR agonist currently in clinical trials for autoimmune diseases, which can sequester RXR receptors and phenocopies the genetic approach using DNRARα T cells and allowing translation into the clinic. We discovered that IRX4204 can enhance in vitro CD4+CD25+Foxp3+ Regulatory T cell (iTreg) generation from naïve CD4+Foxp3- precursors (Figure 1B), suggesting it might increase Treg in vivo, and therefore be therapeutically useful for aGVHD prevention. To determine the effects of IRX4204 in aGVHD, we used two fully MHC mismatched mouse models: (B6 (H-2b) into BALB/c (H-2d) and BALB/c (H-2d) into B6 (H-2b). Recipients treated with IRX4204 had significantly prolonged survival time (Figure 1C&D), reduced weight loss, and better clinical scores compared to vehicle-treated mice. IRX4204 also significantly reduced donor T cell proliferation, effector differentiation and a 2-4 fold reduced production of pro-inflammatory cytokine (IFN-γ, TNF-α). Despite up-regulating gut-homing receptors on donor T cells, intestinal (and liver) GVHD pathology was reduced, which was associated with higher IEC integrity, assessed by po FITC-dextran serum levels. Compared to controls, IRX4204-treated recipients had a higher frequency of Treg in the spleen, mesenteric lymph nodes (p Disclosures Chandraratna: Io Pharmaceuticals: Other: Employed by Io Pharmaceuticals and is a board member, holding the titles of title of President and Chief Scientific Officer, and has ownership interest in Io Pharmaceuticals. .

Background The pathogenesis of food allergy is not completely understood – animal models suggest hepatic mechanisms may be important for immune tolerance to orally ingested antigens, but there is little direct evidence for this in humans. Objectives We investigated whether there is an association between liver dysfunction or transplantation in young children and IgE sensitisation to food. Methods We evaluated paired pre- and post- liver transplant sera from children aged 0–36 months treated at a single centre during 2001–2008. Sera were assayed for total IgE and cow's milk, egg and peanut-specific IgE. We quantified hepatic dysfunction pre-transplant using the Paediatric End-stage Liver Disease (PELD) score. We also assessed 70 children after renal transplant to establish whether any association between liver transplant and food sensitisation was organ specific. Results Paired sera were available from 50 of 94 children who had a liver transplant during the study period. 35 of 50 (70%) had IgE sensitisation (≥0.35 kUa/l) to ≥1 food pre-transplant and 18 (36%) post-transplant (p = 0.001). Ten (20%) children had food-specific IgE levels that carry high probability of challenge-confirmed food allergy pre-transplant. Food sensitisation pre-transplant was associated with severity of liver dysfunction [mean (s.d.) pre-transplant PELD score 1.52 (0.13) in food sensitised, 0.77 (0.22) in non-sensitised children p = 0.004]. Total IgE level was raised in 34/42 (81%) pre-transplant and fell significantly post-transplant. Interview assessment of the parents of 40 children revealed that 13 (33%) had a history consistent with food allergy. These findings were not replicated in the renal transplant group. Conclusions Young children with severe liver dysfunction appear to have a high prevalence of food sensitisation. Hepatic mechanisms may therefore be important for establishing immune tolerance to dietary antigens in humans.

Immune cell activation induces concurrent temporal and spatial retinoic acid signaling, and CD4+ T cell–specific loss of RA signals reduces effector function, migration, and polarity., It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4+ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4+ T cell differentiation and immunity.

Can a patient's genotype provide insight into the mechanistic basis of autoimmune disease? A study integrating epigenetic data with finely mapped disease-associated variants sheds light on how noncoding variants might alter gene expression within specific immune cells, and hints at new possibilities for individualizing treatment of autoimmune rheumatic disorders.

A career path in academic paediatric medicine is an extremely rewarding one, and while not traditionally considered an academic specialty, it offers a wealth of exciting research opportunities. Developing academic paediatrics is becoming increasingly important, as recently reviewed in the Royal College of Paediatrics and Child Health (RCPCH) Turning the Tide report, and developing future leaders in academic paediatrics is a key goal of the academic training pathways. Strategies are being implemented to ensure that the enthusiasm of academic trainees is maintained, and their development into future leaders is secured.

The Royal College of Paediatrics and Child Health’s report highlights challenges to paediatric academic medicine, including loss of senior academics as mentors and role models, and disillusionment of junior trainees poorly equipped to undertake fi rst-rank research. There is evidence for the former, but the latter is belied by a recent national meeting. The fi rst national meeting of paediatric academic trainees was held on April 18, at the Institute of Child Health, London, UK, and was attended by 65 enthusiastic trainees. We did a survey of trainees’ research experiences and future plans. The survey response rate was 74% (48/65). Repondents were from all levels including six academic foundation doctors, 16 academic clinical fellows, 12 PhD fellows, and six lecturers. We noted a strong commitment to academic carreers: 78% of current academics intend to continue research in their next position. In the longer term, 63% hope to work in a clinical academic position, and the remaining 37% plan to work in a clinical position with some teaching and research. This is a strong base from which paediatric academic leaders will surely emerge. However, there was less certainty regarding future academic training and senior jobs. Only 12% believe that there is a good chance of fi nding a clinical academic position within their specialty at their level of training. This reiterates concerns about the loss of senior academic posts raised by the report. It would be good to see more universities commit to supporting paediatric academic postitions in the future. Part-time working also raises specifi c concerns. In the Wellcome Trust 2009 career tracker survey, half of PhD awardees were women, and only 63% continued in academia after completing their award (vs 93% men). Two-thirds of our respondents were women, mirroring recruitment to the specialty, and the majority saw themselves working part-time in the future. However, 88% believed that they would be substantially or somewhat negatively viewed by funding bodies with regards to fl exible working. We believe that the National Institute for Health Researchinspired push to get academic centres certifi ed by the Athena Swan charter is important in supporting paediatric academic training. Rather than disaff ection, the meeting showed paediatric academic trainees engaging with issues that concern their future. The key question is how to support their development into long-term academics? Trainees have a valuable contribution to make to that debate.