Systematic Review: Practices and Programs in Inflammatory Bowel Disease Transition Care.

BACKGROUND: Adolescents with inflammatory bowel disease (IBD) transitioning to adult care is often deemed a challenging period for patients, their carers, and practitioners. The use of structured transition programs is increasingly incorporated into standards of care, yet the optimal format remains unknown. The aim of this study is to carry out a systematic review of structured transition programs and their components to assess the impact on disease-specific and transition-related outcomes. METHODS: A systematic review (PROSPERO ID: CRD42023380846) was performed across 4 databases (PubMed, CINAHL, CENTRAL, and EMBASE) and relevant publications up to March 2023 were reviewed. Studies evaluating either a structured transition program or targeted intervention which also measured a transition- and/or disease-related outcomes were included for evaluation in accordance with the PRISMA statement. RESULTS: Three thousand four hundred and thirty-two articles were identified and 29 included in the final review. A structured transition program was reported in 21 studies and 8 investigated discrete transition-related interventions. The key transition-related outcomes included knowledge, self-efficacy, adherence, clinic attendance, and transition readiness which overall improved with the use of structured transition programs. Similarly, interventions consistently improved relapse/admission rates and corticosteroid use across most studies, although the benefit in hospitalization and surgical rates was less evident. Methodological limitations alongside heterogeneity in study design and outcome measures impacted on the quality of the evidence as assessed by the GRADE rating. CONCLUSIONS: Transition- and medical-related outcomes for adolescents with IBD have been shown to benefit from structured transition programs but practices vary greatly between centers. There is no current standardized transition model for patients with IBD prompting further research to guide future development of guidelines and models of care.

A systematic review was performed to evaluate structured transition programs and their components. Transition- and medical-related outcomes for adolescents with inflammatory bowel disease have been shown to benefit from structured transition programs but the optimal format remains unclear and practices vary in both the clinical and research setting.

Pediatric to Adult Transition in Inflammatory Bowel Disease: Consensus Guidelines for Australia and New Zealand.

BACKGROUND: The incidence of pediatric inflammatory bowel disease (IBD) is rising, and there is an increasing need to support adolescents when they transition to adult care. Evidence supports the use of a structured transition process but there is great variation across Australasia. The study aim was to develop evidence and expert opinion-based consensus statements to guide transitional care services in IBD. METHODS: A modified UCLA-RAND methodology was employed to develop consensus statements. An IBD expert steering committee was formed and a systematic literature review was conducted to guide the drafting of consensus statements. A multidisciplinary group was formed comprising 16 participants (clinicians, nurses, surgeons, psychologists), who anonymously voted on the appropriateness and necessity of the consensus statements using Likert scales (1 = lowest, 9 = highest) with a median ≥7 required for inclusion. Patient support groups, including direct input from young people with IBD, informed the final recommendations. RESULTS: Fourteen consensus statements were devised with key recommendations including use of a structured transition program and transition coordinator, mental health and transition readiness assessment, key adolescent discussion topics, allied health involvement, age for transition, and recommendations for clinical communication and handover, with individualized patient considerations. Each statement reached median ≥8 for appropriateness, and ≥7 for necessity, in the first voting round, and the results were discussed in an online meeting to refine statements. CONCLUSIONS: A multidisciplinary group devised consensus statements to optimize pediatric to adult transitional care for adolescents with IBD. These guidelines should support improved and standardized delivery of IBD transitional care within Australasia.

Transitional care practices for adolescents with inflammatory bowel disease vary across Australasia, and a need for standardized care has been identified. A multidisciplinary team developed Consensus Guidelines to facilitate standardized transition from the pediatric to adult healthcare setting across Australasia.

Transitional care of adolescents with inflammatory bowel disease to adult services varies widely across Australia and New Zealand.

Background and Aim: Children and adolescents account for approximately 14% of inflammatory bowel disease (IBD) diagnoses. At an appropriate age and level of development adolescents with IBD have their care transferred from the pediatric to adult clinical team during a process termed "transition". The study aim was to survey pediatric gastroenterologists throughout Australasia to identify commonality in the transition process to contribute to standardized guideline development. Methods: A descriptive survey captured key variables: transition clinic format, process and infrastructure, transition assessments, and guidelines. The survey was distributed electronically to 59 Pediatric Gastroenterologists throughout Australasia in January 2023. Results: Seventeen (29%) clinicians completed the survey: Australia 13 (76%). New Zealand 4 (24%). Thirteen (76%) respondents had access to a dedicated IBD transition clinic. Adolescents attended transition clinics 1-7 times, and the main processes transferred were: prescription provision, biologic appointments, and adult team contacts. Transition was first discussed age 13-15 years (53%), or 16-18 years (47%), with the main discussion topics including: continuing adherence (88%), smoking (59%), alcohol use (59%), recreational drug use (59%). Transition readiness assessments were done infrequently (24%). The minority (24%) used formal guidelines to inform the transition process, but 15 (88%) considered the development of a standardized Australasian guideline as beneficial/extremely beneficial. Conclusions: This survey highlighted that transition care for adolescents with IBD is variable across Australasia. Australasian guideline development may optimize the transition process for adolescents with IBD and improve their longitudinal outcomes.

Epithelially Restricted Interferon Epsilon Protects Against Colitis.

BACKGROUND & AIMS: Type I interferon (T1IFN) signalling is crucial for maintaining intestinal homeostasis. We previously found that the novel T1IFN, IFNε, is highly expressed by epithelial cells of the female reproductive tract, where it protects against pathogens. Its function has not been studied in the intestine. We hypothesize that IFNε is important in maintaining intestinal homeostasis. METHODS: We characterized IFNε expression in mouse and human intestine by immunostaining and studied its function in the dextran sulfate sodium (DSS) colitis model using both genetic knockouts and neutralizing antibody. RESULTS: We demonstrate that IFNε is expressed in human and mouse intestinal epithelium, and expression is lost in inflammation. Furthermore, we show that IFNε limits intestinal inflammation in mouse models. Regulatory T cell (Treg) frequencies were paradoxically decreased in DSS-treated IFNε-/- mice, suggesting a role for IFNε in maintaining the intestinal Treg compartment. Colitis was ameliorated by transfer of wild-type Tregs into IFNε-/- mice. This demonstrates that IFNε supports intestinal Treg function. CONCLUSIONS: Overall, we have shown IFNε expression in intestinal epithelium and its critical role in gut homeostasis. Given its known role in the female reproductive tract, we now show IFNε has a protective role across multiple mucosal surfaces.

Co-design and Consultation Ensure Consumer Needs Are Met: Building an eHealth Platform for Children with Inflammatory Bowel Disease.

BACKGROUND: Crohn's Colitis Care is an adult inflammatory bowel disease eHealth system. Crohn's Colitis Care required additional pediatric functionality to enable life-long records and mitigate transition inadequacies. AIM: This study describes and evaluates a consensus method developed to ensure consumer needs were met. METHODS: Pediatric-specific functionality and associated resources considered important for inclusion were developed by a clinician consensus group. This group was divided into thematic subgroups and underwent two voting rounds. The content validity index was used to determine items reaching consensus. Children with inflammatory bowel disease and their parents were later shown a descriptive list of non-clinical inclusion topics proposed by the consensus group, and asked to vote on whether topic-related functionality and resources should be included. RESULTS: The consensus process consulted 189 people in total (38 clinicians, 32 children with inflammatory bowel disease and 119 parents). There was agreement across all groups to incorporate functionality and resources pertaining to quality of life, mental health, self-management, and transition readiness; however, divergence was seen for general inflammatory bowel disease facts, your inflammatory bowel disease history, and satisfaction. Cost saw the greatest disparity, being less supported by consumers compared to clinicians. Over 75% of consumers agreed it would be okay for appointments to take longer for survey completion, and > 90% thought Crohn's Colitis Care should allow consumers to ask their treating team questions. CONCLUSIONS: Widespread consumer co-design and consultation were important in unveiling differing perspectives to ensure Crohn's Colitis Care was built to support both consumer and clinician perspectives. Consumers collaborate to create a list of functionality and resources to be included in software (left), influencing the final product build (right).

Disease-specific loss of microbial cross-feeding interactions in the human gut.

Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here, we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metabolic models of prokaryotic metagenome-assembled genomes from over 1600 individuals, MES allows us to identify and rank metabolic interactions that are significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases. When applied to a Crohn's disease case-control study, our approach identifies a lack of species with the ability to consume hydrogen sulfide as the main distinguishing microbiome feature of disease. We propose that our conceptual framework will help prioritize in-depth analyses, experiments and clinical targets, and that targeting the restoration of microbial cross-feeding interactions is a promising mechanism-informed strategy to reconstruct a healthy gut ecosystem.

Bacterial clade-specific analysis identifies distinct epithelial responses in inflammatory bowel disease.

Abnormal immune responses to the resident gut microbiome can drive inflammatory bowel disease (IBD). Here, we combine high-resolution, culture-based shotgun metagenomic sequencing and analysis with matched host transcriptomics across three intestinal sites (terminal ileum, cecum, rectum) from pediatric IBD (PIBD) patients (n = 58) and matched controls (n = 42) to investigate this relationship. Combining our site-specific approach with bacterial culturing, we establish a cohort-specific bacterial culture collection, comprising 6,620 isolates (170 distinct species, 32 putative novel), cultured from 286 mucosal biopsies. Phylogeny-based, clade-specific metagenomic analysis identifies key, functionally distinct Enterococcus clades associated with either IBD or health. Strain-specific in vitro validation demonstrates differences in cell cytotoxicity and inflammatory signaling in intestinal epithelial cells, consistent with the colonic mucosa-specific response measured in patients with IBD. This demonstrates the importance of strain-specific phenotypes and consideration of anatomical sites in exploring the dysregulated host-bacterial interactions in IBD.

Isolated positive deamidated gliadin peptide-IgG has limited diagnostic utility in coeliac disease.

AIM: Deamidated gliadin peptide-IgG (DGP-IgG) antibody serology testing is widely utilised in screening for coeliac disease in Australia; however, it is used sparingly in Europe. The aim of this study was to assess the diagnostic value of a positive DGP-IgG in the setting of a negative tissue transglutaminase-IgA (tTG-IgA) for gastrointestinal pathology among paediatric patients. METHODS: We conducted a retrospective cohort study of all children with an elevated DGP-IgG in the setting of a negative tTG-IgA who underwent gastroscopy over a 48-month period (January 2015-December 2018) at a tertiary paediatric centre. They were identified utilising the electronic pathology database and demographic and clinical data were collected from electronic medical records. Patients who had previously been diagnosed with coeliac disease were on a gluten-free diet or over the age of 18 were excluded from the study. RESULTS: Twenty-six patients with an elevated DGP-IgG in the setting of a negative tTG-IgA underwent gastroscopy. Our study yielded a positive predictive value of 1/26 (3.9% CI 95% 0.7%, 18.9%) for the diagnosis of coeliac disease. Overall, there were 25 histopathological diagnoses including 1 diagnosis of coeliac disease among the total 26 patients who were positive DGP-IgG and negative tTG-IgA and underwent gastroscopy. CONCLUSIONS: Our findings suggest that an isolated positive DGP-IgG has a very low diagnostic yield for coeliac disease in children and may be indicative of other gastrointestinal pathology.

Changes to the Bacterial Microbiome in the Rhizosphere and Root Endosphere of Persea americana (Avocado) Treated With Organic Mulch and a Silicate-Based Mulch or Phosphite, and Infested With Phytophthora cinnamomi.

Plant growth and responses of the microbial profile of the rhizosphere soil and root endosphere were investigated for avocado plants infested or not infested with Phytophthora cinnamomi and the changes were compared in plants grown with various soil additives or by spraying plants with phosphite. Soil treatments were organic mulches or silica-based mineral mulch. Reduction of root growth and visible root damage was least in the infested plants treated with phosphite or mineral mulch applied to the soil. Rhizosphere soils and root endospheres were analyzed for bacterial communities using metabarcoding. Bacterial abundance and diversity were reduced in infested rhizospheres and root endospheres. The presence or absence of mineral mulch resulted in greater diversity and larger differences in rhizosphere community composition between infested and non-infested pots than any other treatment. Some rhizosphere bacterial groups, especially Actinobacteria and Proteobacteria, had significantly higher relative abundance in the presence of Phytophthora. The bacterial communities of root endospheres were lower in abundance than rhizosphere communities and not affected by soil treatments or phosphite but increased in abundance after infection with P. cinnamomi. These findings suggested that the addition of silicate-based mineral mulch protects against Phytophthora root rot, which may be partly mediated through changes in rhizosphere bacterial community composition. However, the changes to the microbiome induced by spraying plants with phosphite are different from those resulting from the application of mineral mulch to the soil.

Review article: the future of microbiome-based therapeutics.

BACKGROUND: From consumption of fermented foods and probiotics to emerging applications of faecal microbiota transplantation, the health benefit of manipulating the human microbiota has been exploited for millennia. Despite this history, recent technological advances are unlocking the capacity for targeted microbial manipulation as a novel therapeutic. AIM: This review summarises the current developments in microbiome-based medicines and provides insight into the next steps required for therapeutic development. METHODS: Here we review current and emerging approaches and assess the capabilities and weaknesses of these technologies to provide safe and effective clinical interventions. Key literature was identified through Pubmed searches with the following key words, 'microbiome', 'microbiome biomarkers', 'probiotics', 'prebiotics', 'synbiotics', 'faecal microbiota transplant', 'live biotherapeutics', 'microbiome mimetics' and 'postbiotics'. RESULTS: Improved understanding of the human microbiome and recent technological advances provide an opportunity to develop a new generation of therapies. These therapies will range from dietary interventions, prebiotic supplementations, single probiotic bacterial strains, human donor-derived faecal microbiota transplants, rationally selected combinations of bacterial strains as live biotherapeutics, and the beneficial products or effects produced by bacterial strains, termed microbiome mimetics. CONCLUSIONS: Although methods to identify and refine these therapeutics are continually advancing, the rapid emergence of these new approaches necessitates accepted technological and ethical frameworks for measurement, testing, laboratory practices and clinical translation.

Impact of a new young adult inflammatory bowel disease transition clinic on patient satisfaction and clinical outcomes.

AIM: The transition from paediatric to adult care for patients with inflammatory bowel disease (IBD) is associated with an increased risk of treatment non-adherence, hospitalizations and emergency department (ED) use. We established a new young adult IBD clinic (YAC) in Melbourne to capture this at-risk population. We aimed to assess patient satisfaction as well as clinical outcomes. METHODS: All patients who attended the YAC between its inception in November 2016 and November 2018 were recruited to our YAC group, 61 patients in total. A control group was selected from the pre-existing adult clinic (AC) at our service, 34 patients in total. IBD-related ED (IBD-ED) visits were collected for all patients. We compared IBD-ED visits in the 2 years before and after attending the clinic for the first time. Patient satisfaction was assessed using the IBD-Patient Satisfaction Questionnaire. RESULTS: There was an overall decrease in IBD-ED visits between the pre-clinic and post-clinic periods in both the YAC (42.9% reduction) and AC (69.2% reduction) (P < 0.001). Patient satisfaction was high amongst both services with YAC patients indicating higher satisfaction with communication (P = 0.015). CONCLUSION: There was a reduction in IBD-ED visits in both the YAC and the AC, high patient satisfaction, and statistically higher satisfaction with communication in the YAC. We speculate the importance of a YAC is to capture those patients in the peri-transitional period at risk of being lost to follow-up or not previously referred for specialist care.

Decade of the dangers of multiple magnet ingestion in children: A retrospective review.

AIM: Magnet ingestion has become more frequent in children as magnetic toys and jewellery have been popularised, with the potential to cause significant morbidity. Our aim was to describe our experience at a tertiary paediatric surgical centre. METHODS: Retrospective review of patients admitted with multiple magnet ingestion (January 2011-December 2020). Division into an intervention group and conservative group. Comparisons included demographics, number of magnets and clinical outcomes. Data analysis with a Student's t-test and ROC Curve, P value of <0.05 was significant. RESULTS: A total of 23 patients were identified with a total of 150 magnets ingested. The majority required an intervention for magnets retrieval (15/23, 65.2%), 11/15 (73.3%) surgical and 4/15 (26.7%) endoscopic. In the surgery group, 6/11 (54%) presented with an initial perforation and 1/11 (9.1%) an entero-enteric fistula. One patient (9.1%) had a multi-site anastomotic leak post-operatively. The conservative group had a significantly lower median number of ingested magnets (2 (2-6) vs. 7 (2-40), P = 0.03) and median length of stay (1 (1-4) vs. 7 (1-24), P = 0.03). ROC curve analysis revealed ingestion of >3 magnets had a sensitivity of 86.7% (95% CI: 62.1-97.6%) and specificity of 87.5% (95% CI: 53.0-99.4%) for requiring an intervention. CONCLUSION: This series highlights a significant morbidity in children with a higher incidence of intervention following ingestion of more than three magnets. There is a strong requirement for the creation and adherence to new legislature involving industry standards.

Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire.

Repeated Plasmodium falciparum infections drive the development of clinical immunity to malaria in humans; however, the immunological mechanisms that underpin this response are only partially understood. We investigated the impact of repeated P. falciparum infections on human γδ T cells in the context of natural infection in Malian children and adults, as well as serial controlled human malaria infection (CHMI) of U.S. adults, some of whom became clinically immune to malaria. In contrast to the predominant Vδ2+ T cell population in malaria-naïve Australian individuals, clonally expanded cytotoxic Vδ1effector T cells were enriched in the γδ T cell compartment of Malian subjects. Malaria-naïve U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the γδ T cell repertoire. Specifically, innate-like Vδ2+ T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas Vδ1+ T cells increased in frequency with repeated infections. Moreover, repeated P. falciparum infection drove waves of clonal selection in the Vδ1+ T cell receptor repertoire that coincided with the differentiation of Vδ1naïve T cells into cytotoxic Vδ1effector T cells. Vδ1+ T cells of malaria-exposed Malian and U.S. individuals were licensed for reactivity to P. falciparum parasites in vitro. Together, our study indicates that repeated P. falciparum infection drives the clonal expansion of an adaptive γδ T cell repertoire and establishes a role for Vδ1+ T cells in the human immune response to malaria.

Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor.

Unlike conventional αß T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)δ1+ and Vδ2+ γδ TCR-mediated ligand recognition, the mode of Vδ3+ TCR ligand engagement is unknown. MHC class I-related protein, MR1, presents vitamin B metabolites to αß T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2- γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vδ3+ TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vδ3+ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.

Emergency Presentations for Gastrostomy Complications Are Similar in Adults and Children.

ABSTRACT: Gastrostomy tube (GT) complications are often managed in the Emergency Department (ED). We aimed to characterize and compare the pattern of ED presentations of GT complications in adults and children. A retrospective chart review of patients with GT complications presenting to 3 Australian EDs in 2 years was undertaken. ED visits for GT complications occurred in 70 GT patients (36 adults, 34 children) with 122 presentations. When comparing adults to children, infections occurred in 21% versus 36%, respectively; P = 0.08, mechanical issues in 48% versus 52%; P = 0.86, vomiting in 23% versus 8%; P = 0.02, and other issues in 7% versus 5%; P = 0.7. Presentation to ED within 28 days of initial GT insertion occurred in 3 (8%) adults and 3 (9%) children, predominantly with tube dislodgement. GT complications seen in ED are predominantly infectious and mechanical in nature, with an increased frequency of vomiting in adults when compared with children.

The future is now? Clinical and translational aspects of "Omics" technologies.

Big data has become a central part of medical research, as well as modern life generally. "Omics" technologies include genomics, proteomics, microbiomics and increasingly other omics. These have been driven by rapid advances in laboratory techniques and equipment. Crucially, improved information handling capabilities have allowed concepts such as artificial intelligence and machine learning to enter the research world. The COVID-19 pandemic has shown how quickly information can be generated and analyzed using such approaches, but also showed its limitations. This review will look at how "omics" has begun to be translated into clinical practice. While there appears almost limitless potential in using big data for "precision" or "personalized" medicine, the reality is that this remains largely aspirational. Oncology is the only field of medicine that is widely adopting such technologies, and even in this field uptake is irregular. There are practical and ethical reasons for this lack of translation of increasingly affordable techniques into the clinic. Undoubtedly, there will be increasing use of large data sets from traditional (e.g. tumor samples, patient genomics) and nontraditional (e.g. smartphone) sources. It is perhaps the greatest challenge of the health-care sector over the coming decade to integrate these resources in an effective, practical and ethical way.

Microbiome in health and disease.

There has been an exponential rise in research into the microbiota of the human gastrointestinal tract, particularly of the genomic content (the microbiome). The vast number of micro-organisms residing in our gut has an integral role in essential processes, including growth and development. Probiotics, live micro-organisms with putative benefits on health have become ubiquitous as treatments for many conditions, despite often limited robust clinical trial data. However, the resurgence of faecal microbial transplantation as an effective treatment modality provides further promise that manipulation of our microbiome can have clinical benefits. This review will present the recent evidence for the role of the microbiome in development and growth, and focus on the evidence for its manipulation in paediatric diseases. We will show that while there is promising data in specific diseases, there remain many unanswered questions. Only through a deeper understanding of our complex internal ecosystem will we be able to move to the next stage of targeted microbial therapy.

Histology at diagnostic gastroscopy predicts outcome after intestinal resection in pediatric Crohn's disease.

BACKGROUND AND AIM: Pediatric Crohn's disease (CD) has been shown to have a high recurrence rate following surgical resection. Risk factors for postoperative CD recurrence in children are not well known. The aim of this study was to identify factors influencing postoperative recurrence in pediatric CD. METHODS: Pediatric CD patients who underwent surgical resection with primary anastomosis with a minimum follow up of 2 years were identified from databases at the Royal London Hospital and Massachusetts General Hospital. Patients were subdivided into a recurrence group defined by clinical, endoscopic, histological, radiological and/or surgical outcomes, and a nonrecurrence group. Patient demographics, initial gastroscopy and colonoscopy findings, Paris classification, and preoperative and postoperative pharmacotherapy were analyzed. RESULTS: Ninety-six children who underwent an ileal or ileocolonic resection with primary anastomosis were identified. Fifty-seven children had postoperative recurrence. Recurrence was associated with abnormal initial gastroscopy findings (P = 0.0077), ileocolonic disease location (P = 0.03), and perianal disease involvement (P = 0.04). Patients with abnormal initial gastroscopy had higher rates of relapse (hazard ratio 3.42, 95% confidence interval [CI] [1.86-6.30], P = 0.001). Multivariate analysis demonstrated that abnormal diagnostic gastroscopy histology was a significant independent predictor of postoperative recurrence in this cohort (odds ratio 1.33, 95% CI [1.04-1.70], P = 0.024). The most common histological abnormality was non-Helicobacter gastritis, found in 29/46 (63%). CONCLUSION: This dual-center study has shown that the presence of upper gastrointestinal tract inflammation, especially non-Helicobacter gastritis, at the time of diagnosis, is associated with an increased risk of postoperative recurrence in pediatric CD.

A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1.

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I-like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR-MR1-antigen complex starkly contrasts with all other TCR-MHC and TCR-MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.