Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

Proposal regarding potential causes related to certain complications with dental implants and adjacent natural teeth: Physics applied to prosthodontics.

PURPOSE: Complications can and do occur with implants and their restorations with causes having been proposed for some single implant complications but not for others. METHODS: A review of pertinent literature was conducted. A PubMed search of vibration, movement, and dentistry had 175 citations, while stress waves, movement, and dentistry had zero citations as did stress waves, movement. This paper discusses the physics of vibration, elastic and inelastic collision, and stress waves as potentially causative factors related to clinical complications. RESULTS: Multiple potential causes for interproximal contact loss have been presented, but it has not been fully understood. Likewise, theories have been suggested regarding the intrusion of natural teeth when they are connected to an implant as part of a fixed partial denture as well as intrusion when a tooth is located between adjacent implants, but the process of intrusion, and resultant extrusion, is not fully understood. A third complication with single implants and their crowns is abutment screw loosening with several of the clinical characteristics having been discussed but without determining the underlying process(es). CONCLUSIONS: Interproximal contact loss, natural tooth intrusion, and abutment screw loosening are common complications that occur with implant retained restorations. Occlusion is a significant confounding variable. The hypothesis is that vibration, or possibly stress waves, generated from occlusal impact forces on implant crowns and transmitted to adjacent teeth, are the causative factors in these events. Since occlusion appears to play a role in these complications, it is recommended that occlusal contacts provide centralized stability on implant crowns and not be located on any inclined surfaces that transmit lateral forces that could be transmitted to an adjacent tooth and cause interproximal contact loss or intrusion. The intensity, form, and location of proximal contacts between a natural tooth located between adjacent single implant crowns seem to play a role in the intrusion of the natural tooth. Currently, there is a lack of information about the underlying mechanisms related to these occurrences and research is needed to define any confounding variables.

Exploring the health care utilization of children and youth in the care of child welfare: a retrospective matched cohort study.

BACKGROUND: Children and youth whose lives intersect with child welfare systems are amongst the most vulnerable paediatric populations. Despite the increased rates of chronic conditions, these children and youth often experience unmet health care needs. OBJECTIVES: To examine patterns of health care utilization from birth for children and youth in the care of a child welfare authority. METHODS: This retrospective matched cohort design study examined children/youth aged 0-18 who had visited a paediatric tertiary care facility from 2016 April 1 to 2017 March 31 and had "social worker" documented as their guardian. A control cohort was matched based on age and sex. Primary outcomes of interest included primary health care, emergency, outpatient, and inpatient visits. Visits for immunizations, physiological development, well-baby checks, mental health, and oral health were also examined. RESULTS: A total of 200 cases and 200 controls were included in our cohort. No statistically significant differences were found between primary care visits, well-baby checks, inpatient admissions, outpatient mental health visits, or immunizations for children in care in comparison to their controls. There was a significant difference in oral health visits, lack of physiological development, and emergency department visits for children in care when compared to their controls. CONCLUSIONS: Our study revealed disparities in health care utilization amongst children in the care of child welfare in comparison to those who are not, highlighting the need for improved practice, policy, and research initiatives. A collaborative data collection/sharing system is needed to identify and track the health care of this vulnerable population.

Children and youth whose lives intersect with child welfare systems are amongst the most vulnerable pediatric populations. Despite the increased rates of chronic health conditions, these children and youth often experience unmet health care needs. Using a retrospective matched cohort design, we sought to examine patterns of health care utilization from birth to age 18 for children and youth in the care of a child welfare authority in comparison to children/youth who were not in the care of child welfare. No statistically significant differences were found between primary care visits, well-baby checks, inpatient admissions, outpatient mental health visits, or immunizations for children in care when compared to their counterparts not in care. There was a significantly higher number of oral health visits, physiological development concerns, and emergency department visits for children in care when compared to their controls. Our study revealed differences in health care use amongst children in the care of a child welfare in comparison to those who are not, highlighting the need for improved practice, policy and research initiatives. A collaborative data collection and sharing system is needed to help accurately identify and track the health care use of this vulnerable population.

Enhancing researcher capacity to engage youth in research: Researchers' engagement experiences, barriers and capacity development priorities.

BACKGROUND: There is increasing emphasis on engaging youth in research about youth, their needs, experiences and preferences, notably in health services research. By engaging youth as full partners, research becomes more feasible and relevant, and the validity and richness of findings are enhanced. Consequently, researchers need guidance in engaging youth effectively. This study examines the experiences, needs and knowledge gaps of researchers. METHODS: Eighty-four researchers interested in youth engagement training were recruited via snowball sampling. They completed a survey regarding their youth engagement experiences, attitudes, perceived barriers and capacity development needs. Data were analysed descriptively, and comparisons were made based on current engagement experience. RESULTS: Participants across career stages and disciplines expressed an interest in increased capacity development for youth engagement. They had positive attitudes about the importance and value of youth engagement, but found it to be complex. Participants reported requiring practical guidance to develop their youth engagement practices and interest in a network of youth-engaged researchers and on-going training. Those currently engaging youth were more likely to report the need for greater appreciation of youth engagement by funders and institutions. CONCLUSIONS: Engaging youth in research has substantial benefits. However, skills in collaborating with youth to design, conduct and implement research have to be learned. Researchers need concrete training and networking opportunities to develop and maximize these skills. They also need mechanisms that formally acknowledge the value of engagement. Researchers and those promoting youth engagement in research are encouraged to consider these findings in their promotion and training endeavours.

INNOVATE Research: Impact of a workshop to develop researcher capacity to engage youth in research.

BACKGROUND: Engaging youth in research provides substantial benefits to research about youth-related needs, concerns and interventions. However, researchers require training and capacity development to work in this manner. METHODS: A capacity-building intervention, INNOVATE Research, was co-designed with youth and adult researchers and delivered to researchers in three major academic research institutions across Canada. Fifty-seven attendees participated in this research project evaluating youth engagement practices, attitudes, perceived barriers, and perceived capacity development needs before attending the intervention and six months later. RESULTS: The intervention attracted researchers across various career levels, roles and disciplines. Participants were highly satisfied with the workshop activities. Follow-up assessments revealed significant increases in self-efficacy six months after the workshop (P = .035). Among possible barriers to youth engagement, four barriers significantly declined at follow-up. The barriers that decreased were largely related to practical knowledge about how to engage youth in research. Significantly more participants had integrated youth engagement into their teaching activities six months after the workshop compared to those who were doing so before the workshop (P = .007). A large proportion (71.9%) of participants expressed the need for a strengthened network of youth-engaged researchers; other future capacity-building approaches were also endorsed. CONCLUSIONS: The INNOVATE Research project provided improvements in youth engagement attitudes and practices among researchers, while lifting barriers. Future capacity-building work should continue to enhance the capacity of researchers to engage youth in research. Researchers notably pointed to the need to establish a network of youth-engaged researchers to provide ongoing, sustainable gains in youth engagement.

A sequence conserved between CD5 and CD6 binds an FERM domain and exerts a restraint on T-cell activation.

CD5 and CD6 are related surface receptors that limit and promote T-cell responses. Co-stimulatory effects of CD6 depend on binding a cell surface ligand, CD166, and recruitment of the intracellular adaptor proteins GADS and SLP-76 by C-terminal phosphotyrosines. We have continued to identify interactions of CD5 and CD6 to understand their roles in T-cell activation. In a screen to identify binding partners for peptides containing a cytoplasmic sequence, SDSDY conserved between CD5 and CD6, we identified ezrin radixin moesin (ERM) proteins, which link plasma membrane proteins to actin. Purified radixin FERM domain bound directly to CD5 and CD6 SDSDY peptides in a phosphorylation-dependent manner (KD = 0·5-2 µm) at 37°. In human T-cell blasts, mutation of the CD6 SDSDY sequence enhanced CD69 expression in response to CD3 monoclonal antibody. In this proximal readout, interactions of the SDSDY sequence were dominant compared with the C-terminal tyrosines of CD6. In contrast, in a more downstream readout, interleukin-2 expression, in response to immobilized CD3 and CD6 monoclonal antibodies, the C-terminal tyrosines were dominant. The data suggest that varying functional effects of CD6 and potentially CD5 depend on interactions of different cytoplasmic regions with the cytoskeleton and alter depending on the stimuli.

Addition of the C-terminus of CD6 to a chimeric antigen receptor enhances cytotoxicity and does not compromise expression.

T cells expressing chimeric antigen receptors (CARs) are a promising new cancer immunotherapy that has now reached the clinic. CARs are synthetic receptors that redirect T cells towards a tumour-associated antigen and activate them through various fused signalling regions, for example derived from CD3ζ, 4-1BB or CD28. Analysis of the optimal combination of CAR components including signalling domains is not yet comprehensive and may vary with the particular application. The C-terminus of the T-cell surface receptor CD6 is critical for its co-stimulatory effects and signals through two phospho-tyrosine motifs that bind to the intracellular adaptor proteins GADS and SLP-76. Addition of the C terminus of CD6 did not compromise CAR expression, showing it was a stable moiety that can be used independently of the native receptor. A third-generation CAR containing 4-1BB, CD3ζ and the C terminus of CD6 (4-1BBz-CD6) enhanced interferon-γ release and cytotoxicity when compared with the second-generation 4-1BB CD3ζ (4-1BBz) CAR. The CD6 C terminus is a valuable addition to potential components for modular design of CARs to improve effector function, particularly cytotoxicity.

Domain-specific CD6 monoclonal antibodies identify CD6 isoforms generated by alternative-splicing.

The characterization of the architecture, structure and extracellular interactions of the CD6 glycoprotein, a transmembrane receptor expressed in medullary thymocytes and all mature T-cell populations, has been enhanced by the existence of monoclonal antibodies (mAbs) that specifically recognize the various scavenger receptor cysteine-rich (SRCR) domains of the ectodomain. Using engineered isoforms of CD6 including or excluding each of the three SRCR domains, either expressed at the membranes of cells or in soluble forms, we provide conclusive and definitive evidence that domain 2 of CD6, previously not identifiable, can be recognized by the CD6 mAbs OX125 and OX126, and that OX124 targets domain 3 and can block the interaction at the cell surface of CD6 with its major ligand CD166. Alternative splicing-dependent CD6 isoforms can now be confidently identified. We confirm that following T-cell activation there is a partial replacement of full-length CD6 by the CD6Δd3 isoform, which lacks the CD166-binding domain, and we find no evidence for the expression of other CD6 isoforms at the mRNA or protein levels.

CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action.

CD6 is a type I T-cell surface receptor that modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab™), which has reached the clinic for treatment of autoimmune disease. We characterized molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action. Epitope mapping using the crystal structure of CD6 to design mutants identified two distinct binding sites on different faces of domain 1, one containing residue R77, crucial for MT605 and T12.1 binding and the other, E63, which is crucial for itolizumab and MEM98. Analysis of binding kinetics revealed that itolizumab has a lower affinity compared with other CD6 domain 1 mAbs. We compared potential agonistic (triggering) and antagonistic (blocking) properties of CD6 mAbs in assays where the mechanism of action was well defined. CD6 domain 1 and 3 mAbs were equally effective in triggering interleukin-2 production by a cell line expressing a chimeric antigen receptor containing the extracellular region of CD6. CD6 domain 1 mAbs hindered binding of multivalent immobilized CD166 but were inferior compared with blocking by soluble CD166 or a CD6 domain 3 mAb. Characterization of CD6 mAbs provides an insight into how their functional effects in vivo may be interpreted and their therapeutic use optimized.

The SIRP family of receptors and immune regulation.

The immune system must be highly regulated to obtain optimal immune responses for the elimination of pathogens without causing undue side effects. This tight regulation involves complex interactions between membrane proteins on leukocytes. Members of the signal-regulatory protein (SIRP) family, which are expressed mainly by myeloid cells, provide one example of these regulatory membrane proteins. There are three SIRP-family genes that encode proteins that have similar extracellular regions but different signalling potentials, and are therefore known as 'paired receptors'. In this Review, we describe recent studies defining the ligands of the SIRP-family members, with particular emphasis on relating the molecular interactions of these proteins to their role in immune-cell regulation.

A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T-cell activation.

Signalling lymphocyte activation molecule (SLAM) family members regulate activation and inhibition in the innate and adaptive immune systems. Genome-wide association studies identified their genetic locus (1q23) as highly polymorphic and associated with susceptibility to systemic lupus erythematosus (SLE). Here we show that the Val602 variant of the non-synonymous single nucleotide polymorphism (SNP) rs509749 in the SLAM family member CD229 (Ly9, SLAMF3) has a two-fold lower affinity compared with the SLE-associated Met602 variant for the small adaptor protein SAP. Comparison of the two variants in T-cell lines revealed the Val602 variant to be significantly more highly expressed than CD229 Met602 . Activation was diminished in cells expressing CD229 Val602 compared with CD229 Met602 as measured by up-regulation of CD69. There was no correlation between homozygosity at rs509749 and activation in peripheral blood mononuclear cells from healthy donors. These findings identify potential mechanisms by which a single SNP can perturb fine-tuning in the immune system with significant functional consequences.

Invasive carnivores alter ecological function and enhance complementarity in scavenger assemblages on ocean beaches.

Species composition is expected to alter ecological function in assemblages if species traits differ strongly. Such effects are often large and persistent for nonnative carnivores invading islands. Alternatively, high similarity in traits within assemblages creates a degree of functional redundancy in ecosystems. Here we tested whether species turnover results in functional ecological equivalence or complementarity, and whether invasive carnivores on islands significantly alter such ecological function. The model system consisted of vertebrate scavengers (dominated by raptors) foraging on animal carcasses on ocean beaches on two Australian islands, one with and one without invasive red foxes (Vulpes vulpes). Partitioning of scavenging events among species, carcass removal rates, and detection speeds were quantified using camera traps baited with fish carcasses at the dune-beach interface. Complete segregation of temporal foraging niches between mammals (nocturnal) and birds (diurnal) reflects complementarity in carrion utilization. Conversely, functional redundancy exists within the bird guild where several species of raptors dominate carrion removal in a broadly similar way. As predicted, effects of red foxes were large. They substantially changed the nature and rate of the scavenging process in the system: (1) foxes consumed over half (55%) of all carrion available at night, compared with negligible mammalian foraging at night on the fox-free island, and (2) significant shifts in the composition of the scavenger assemblages consuming beach-cast carrion are the consequence of fox invasion at one island. Arguably, in the absence of other mammalian apex predators, the addition of red foxes creates a new dimension of functional complementarity in beach food webs. However, this functional complementarity added by foxes is neither benign nor neutral, as marine carrion subsidies to coastal red fox populations are likely to facilitate their persistence as exotic carnivores.

Signal-regulatory protein α from the NOD mouse binds human CD47 with an exceptionally high affinity-- implications for engraftment of human cells.

One common way to study human leucocytes and cancer cells in an experimental in vivo situation is to use mice that have been genetically engineered to lack an immune system and prevent human cell rejection. These mice lack CD132 and either RAG2 or the catalytic subunit of the DNA-dependent protein kinase, to make the mice deficient in lymphocytes and natural killer cells. The NOD mouse strain provides a better background for engraftment than other strains due to stronger engagement of the signal-regulatory protein-α (SIRPα) inhibitory receptor with human CD47 (hCD47) resulting in a 'don't-eat-me' signal. To determine the molecular parameters that determine this major functional effect in the NOD mouse we measured the affinity of hCD47 for SIRPα from various mouse strains. Human CD47 bound SIRPα from the NOD mouse with an affinity 65 times greater than SIRPα from other mouse strains. This is due mainly to the NOD SIRPα lacking two amino acids in domain 1 compared with other mouse strains. Remarkably the SIRPα(NOD) binds hCD47 with 10 times the affinity of the syngeneic hCD47/hSIRPα interaction. This affinity is outside the normal range for affinities for leucocyte surface protein interactions and raises questions as to what is the optimal affinity of this interaction for engraftment and what other xenogeneic interactions involved in homeostasis may also not be optimal.

Rethinking sexual violence labels: exploring the impact of 'victim' and 'survivor' discourse.

Background: Universities' responses to sexual violence have faced scrutiny for their lack of proactiveness and their failure to address campus socio-cultural norms that contribute to rape myth acceptance. The labels victim and survivor play a crucial role in shaping attitudes toward sexual violence, but there is limited research on how university students perceive these labels.Objective: This paper explores sexual violence labels and their role in perpetuating rape culture. Undergraduate university students' beliefs on using the label survivor instead of victim to describe someone who has experienced sexual violence were examined to consider how these labels create societal discourse on sexual violence.Method: The study draws on qualitative data collected from undergraduate students in Canada and the United States through open-response questions in an interactive textbook. Data were analysed and interpreted using a multi-method approach that combined principles of Critical Discourse Analysis and Feminist Poststructuralism. Direct quotes and word clouds from participants' responses are used as evidence and to visually display discourse.Results: Findings revealed that participants recognised the negative societal discourses associated with the label victim and supported using survivor to challenge perceptions of sexual violence. Despite this, participants expressed hesitancy to adopt the label survivor because of the potential negative implications, such as the label promoting the allocation of individual blame, increasing barriers to justice, and reducing the perceived severity of sexual violence.Conclusions: This study underscores the complexities of sexual violence labels, the influence of language in shaping societal perceptions, and the need for a more comprehensive and equitable approach to responding to sexual violence.

Dichotomy of Labels and Nuanced Perceptions: Sexual violence labels shape identity perceptions. Participants dichotomised the labels victim and survivor, associating one with negative attributes and the other with positive attributes. However, nuanced views of how people perceive and identify with these labels challenge distinct categories. Victims being negatively perceived, while survivors are admired for their resiliency highlights complexities in societal expectations that may not fully address the underlying determinants of sexual violence.Role of Language in Reproduction of Rape Culture: Poststructuralist theories emphasise the role of language in the production and maintenance of discourse. The study shows that victim discourse is steeped in rape myths. The historical discourse surrounding the label may contribute to the perpetuation of negative attitudes and behaviours toward victims of sexual violence. The emergence of the label survivor reflects a societal shift, but findings suggest this may lead to societal complacency towards sexual violence.Spectrum of Severity and Societal Empathy: Participants' understanding of sexual violence as a spectrum of severity may lead to unequal levels of empathy and support. This discourse creates positions of dominance and oppression, potentially marginalising certain groups who are disproportionately affected by sexual violence. The study highlights how severity discourse can influence institutional agendas and may result in political and institutional neglect of sexual violence.

Interprofessional collaboration between health professional learners when breaking bad news: a scoping review of teaching approaches.

OBJECTIVE: The objective of this scoping review was to examine teaching approaches used to teach interprofessional health professional learners how to break bad news collaboratively. INTRODUCTION: When breaking bad news, health professionals must be equipped to deliver it skillfully and collaboratively; however, the literature shows that this skill receives little attention in program curricula. Consequently, health professionals can feel inadequately prepared to deliver bad news, which may lead to increased burnout, distress, and compassion fatigue. INCLUSION CRITERIA: Studies that describe teaching approaches used to teach learners how to break bad news collaboratively were considered for inclusion. Studies must have included 2 or more undergraduate and/or postgraduate learners working toward a professional health or social care qualification/degree at a university or college. Studies including lay, complementary and alternative, or non-health/social care learners were excluded. Due to the primary language of the research team, only English articles were included. METHODS: The JBI 3-step process was followed for developing the search. Databases searched included MEDLINE (Ovid), CINAHL (EBSCOhost), Embase, Education Resource Complete (EBSCOhost), and Social Work Abstracts (EBSCOhost). The initial search was conducted on February 11, 2021, and was updated on May 17, 2022. Title and abstract screening and data extraction were completed by 2 independent reviewers. Disagreements were resolved through discussion or with a third reviewer. Results are presented in tabular or diagrammatic format, together with a narrative summary. RESULTS: Thirteen studies were included in the scoping review, with a range of methodologies and designs (pre/post surveys, qualitative, feasibility, mixed methods, cross-sectional, quality improvement, and methodological triangulation). The majority of papers were from the United States (n=8; 61.5%). All but 1 study used simulation-enhanced interprofessional education as the preferred method to teach interprofessional cohorts of learners how to break bad news. The bulk of simulations were face-to-face (n=11; 84.6%). Three studies (23.1%) were reported as high fidelity, while the remainder did not disclose fidelity. All studies that used simulation to teach students how to break bad news utilized simulated participants/patients to portray patients and/or family in the simulations. The academic level of participants varied, with the majority noted as undergraduate (n=7; 53.8%); 3 studies (23.1%) indicated a mix of undergraduate and graduate participants, 2 (15.4%) were graduate only, and 1 (7.7%) was not disclosed. There was a range of health professional programs represented by participants, with medicine and nursing equally in the majority (n=10; 76.9%). CONCLUSIONS: Simulation-enhanced interprofessional education was the most reported teaching approach to teach interprofessional cohorts of students how to break bad news collaboratively. Inconsistencies were noted in the language used to describe bad news, use of breaking bad news and interprofessional competency frameworks, and integration of interprofessional education and simulation best practices. Further research should focus on other interprofessional approaches to teaching how to break bad news; how best to incorporate interprofessional competencies into interprofessional breaking bad news education; whether interprofessional education is enhancing collaborative breaking bad news; and whether what is learned about breaking bad news is being retained over the long-term and incorporated into practice. Future simulation-specific research should explore whether and how the Healthcare Simulation Standards of Best Practice are being implemented and whether simulation is resulting in student satisfaction and enhanced learning.

The impact of the COVID-19 pandemic on primary care physicians and nurses in Nova Scotia: a qualitative exploratory study.

BACKGROUND: The COVID-19 pandemic has brought immense disruption worldwide, dramatically altering the ways we live, work and learn on a day-to-day basis; however, few studies have investigated this from the perspective of primary care providers. In this study, we sought to explore the experiences of primary care providers in the province of Nova Scotia, with the intention of understanding the impact of the COVID-19 pandemic on primary care providers' ability to provide care, their information pathways, and the personal and professional impact of the pandemic. METHODS: We conducted an exploratory qualitative research study involving semistructured interviews conducted via Zoom videoconferencing or telephone with primary care providers (physicians, nurse practitioners and family practice nurses) who self-identified as working in primary health care in Nova Scotia from June 2020 to April 2021. We performed a thematic analysis involving coding and classifying data according to themes. Emergent themes were then interpreted by seeking commonalties, divergence, relationships and overarching patterns in the data. RESULTS: Twenty-four primary care providers were interviewed. Subsequent analysis identified 4 interrelated themes within the data: disruption to work-life balance, disruptions to "non-COVID-19" patient care, impact of provincial and centralized policies, and filtering and processing an influx of information. INTERPRETATION: Our findings showed that managing a crisis of this magnitude requires coordination and new ways of working, balancing professional and personal life, and adapting to already implemented changes (i.e., virtual care). A specific primary care pandemic response plan is essential to mitigate the impact of future health care crises.

Cytomegalovirus e127 protein interacts with the inhibitory CD200 receptor.

CD200 is a cell surface glycoprotein that binds an inhibitory receptor (CD200R) on myeloid cells. CD200 orthologues are present in many species of virus, and we show that the rat cytomegalovirus CD200 orthologue (e127) is expressed at the cell surface on infected cells. It binds the host CD200R with the same affinity as that of the host protein, and thus this protein acts as a close mimic of the host protein and has the potential to downregulate immune responses to the virus.

A ligand for CD5 is CD5.

Recognition by scavenger receptor cysteine-rich domains on membrane proteins regulates innate and adaptive immune responses. Two receptors expressed primarily on T cells, CD5 and CD6, are linked genetically and are structurally similar, both containing three scavenger receptor cysteine-rich domains in their extracellular regions. A specific cell surface interaction for CD5 has been difficult to define at the molecular level because of the susceptibility of CD5 protein to denaturation. By using soluble CD5 purified at neutral pH to preserve biological activity, we show that CD5 mediates species-specific homophilic interactions. CD5 domain 1 only is involved in the interaction. CD5 mAbs that have functional effects in humans, rats, and mice block homophilic binding. Ag-specific responses by mouse T cells in vitro were increased when engagement of human CD5 domain 1 was inhibited by mutation or by IgG or Fab fragment from a CD5 mAb. This showed that homophilic binding results in productive engagement. Enhancement of polyclonal immune responses of rat lymph node cells by a Fab fragment from a CD5 mAb shown to block homophilic interactions provided evidence that the extracellular region of CD5 regulates inhibition in normal cells. These biochemical and in vitro functional assays provide evidence that the extracellular region of CD5 regulates immunity through species-specific homophilic interactions.