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Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular organisms is hypothesized. While mARS complexes in lower eukaryotes may enhance efficiency of aminoacylation, little evidence exists to support a similar role in chordates or other higher eukaryotes. Rather, mARS complexes are reported to regulate multiple and variegated cellular processes that include angiogenesis, apoptosis, inflammation, anaphylaxis, and metabolism. Because all such processes are critical components of immune homeostasis, it is important to understand the role of mARS complexes in immune regulation. Here we provide a conceptual analysis of the current understanding of mARS complex dynamics and emerging mARS complex roles in immune regulation, the increased understanding of which should reveal therapeutic targets in immunity and immune-mediated disease.

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Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.

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BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4. SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays. RESULTS: The primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4. CONCLUSIONS: Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.

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BACKGROUND: Left bundle branch pacing (LBBP) is a developing method of native conduction pacing, but cases of injury to the septal perforator arteries during implantation have been reported. Knowing the distance between the His bundle and the first septal perforator artery can help operators implant LBBP leads more safely. METHODS: Using previously performed coronary CT angiography (CCTA) studies, the distance between the His bundle and the first septal perforator was measured. RESULTS: A total of 50 CCTA studies were included. The mean distance from the His bundle to the first septal perforator (His-SP) along the line connecting the His bundle to the RV apex (His-RV apex) was 27.17 ± 7.7 mm with a range of 13.0 to 44.7 mm. The distance was greater than 2.0 cm in 84% of patients. To standardize this distance among patients with varying cardiac structures, the ratio between the His-SP distance and the His-RV Apex distance was also measured. The mean His-SP:His-RV Apex was 0.302 and the median was 0.298. Eighty-six percent of patients had a ratio of greater than 0.20. CONCLUSION: Using this information, operators can aim to implant LBBP leads within 2.0 cm of the His bundle or 20% of the distance between the His bundle and the RV apex with minimal risk of causing vascular injury.

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Introduction: Hookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4 + Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi, the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection. Methods: Female BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation. Results: Treatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c +CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups. Discussion: All in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.

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BACKGROUND: The existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden. METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer. RESULTS: Elevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism-a well-established inflammatory pathway-and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice. CONCLUSION: GPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.

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A 48-year-old woman underwent preoperative cardiac testing prior to gastric bypass. She was incidentally found to have a right atrial mass on transthoracic echocardiography. Subsequent cardiac magnetic resonance confirmed this finding. She underwent excision of the mass. Tissue pathology revealed ectopic hepatic tissue. (Level of Difficulty: Advanced.).

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OBJECTIVE: Computational modeling has been shown to be a useful tool for simulating representative motorsport impacts and analyzing data for relative injury risk assessment. Previous studies have used computational modeling to analyze the probability of injury in specific regions of a 50th percentile male driver. However, NASCAR drivers can represent a large range in terms of size and female drivers are becoming increasingly more common in the sport. Additionally, motorsport helmets can be outfitted with external attachments, or enhanced helmet systems (EHS), whose effect is unknown relative to head and neck kinematics. The current study expands on this previous work by incorporating the F05-OS and M95-OS into the motorsport environment in order to determine correlations between metrics and factors such as PDOF, resultant ΔV occupant size, and EHS. METHODS: A multi-step computational process was used to integrate the Global Human Body Models Consortium family of simplified occupant models into a motorsport environment. This family included the 5th percentile female (F05-OS), 50th percentile male (M50-OS), and 95th percentile male (M95-OS), which provide a representative range for the size and sex of drivers seen in NASCAR's racing series'. A series of 45 representative impacts, developed from real-world crash data, and set of observed on-track severe impacts were conducted with these models. These impacts were run in triplicate for three helmet configurations: bare helmet, helmet with visor, helmet with visor and camera. This resulted in 450 total simulations. A paired t-test was initially performed as an exploratory analysis to study the effect of helmet configuration on 10 head and neck injury metrics. A mixed-effects model with unstructured covariance matrix was then utilized to correlate the effect between five independent variables (resultant ΔV, body size, helmet configuration, impact quadrant, and steering wheel position) and a selection of 25 metrics. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Risk estimates from the M50-OS with bare helmet were used as reference values to determine the effect of body size and helmet configuration. The paired t-test found significance for helmet configuration in select head-neck metrics, but the relative increase in these metrics was low and not likely to increase injury risk. The mixed-effects model analyzed statistical relationships across multiple types of variables. Within the mixed-effects model, no significance was found between helmet configuration and metrics. The greatest effect was found from resultant ΔV, body size, and impact quadrant. CONCLUSIONS: Overall, smaller drivers showed statistically significant reductions in injury metrics, while larger drivers showed statistically significant increases. Lateral impacts showed the greatest effect on neck metrics and, on average, showed decreases for head metrics related to linear acceleration and increases for head metrics related to angular velocity. HBM parametric studies such as this may provide an avenue to assist injury detection for motorsport incidents, improve triage effectiveness, and assist in the development of safety standards.

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BACKGROUND: Neoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination. METHODS: We report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone. RESULTS: Out of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3-4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV. CONCLUSIONS: These results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.

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In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αß T cell receptor-expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8+ T cell populations (CD8+NK1.1+) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8+NK1.1- T cells. Adoptive transfer of CD8+NK1.1+ cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8+NK1.1- cells. Freshly isolated human CD8+CD61+ T cells exhibited heightened allogeneic killing activity in comparison to CD8+CD61- T cells or total peripheral blood mononuclear cells (PBMCs). To determine whether this subset might improve the antitumor efficacy of CAR T cell therapy against solid tumors, we compared bulk PBMCs, CD8+CD161-, and CD8+CD161+ T cells transduced with a human epidermal growth factor receptor-2 (HER2)-specific CAR construct. In vitro, CD8+CD161+ CAR-transduced T cells killed HER2+ targets faster and with greater efficiency. Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2+ pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.

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BACKGROUND: The Merit-Based Incentive Payment System adjusts clinician payments based on a performance score that includes cost measures. With the Centers for Medicare & Medicaid Services, we developed a novel cost measure that compared interventional cardiologists on a targeted set of costs related to elective percutaneous coronary intervention (PCI). We describe the measure and compare it to a hypothetical version including all expenditures post-PCI. METHODS: Measure development was guided by 39 clinician experts. They identified services within 30 days of PCI that could be potentially affected by the interventional cardiologist. Expenditures for these PCI-related services were included as measure costs in a process termed service assignment. We used 1 year of Medicare claims to calculate clinician scores using the final measure that included only PCI-related costs (with service assignment) and a hypothetical version that included all costs post-PCI (without service assignment). We calculated reliability for both measures. This marker of precision breaks measure variance into signal (difference between clinicians) versus noise (difference between PCI episodes for a clinician). We also determined the change in clinician performance quintile between measures. RESULTS: We identified 100 992 elective outpatient PCI episodes from May 2, 2016, to May 1, 2017. Total Medicare expenditures within 30 days of PCI averaged $13 234. After excluding costs unrelated to PCI, average cost was $10 966. For individual clinicians, mean reliability for the hypothetical measure without service assignment was 0.36. After service assignment, final measure reliability increased to 0.53. When evaluated as clinician groups, reliability increased from 0.43 to 0.73 following service assignment. Approximately 66% (2340 of 3527) of clinicians were reclassified into a different performance quintile after excluding unrelated costs. CONCLUSIONS: The elective outpatient PCI cost measure had increased precision and reclassified clinician performance relative to a hypothetical version that included total expenditures.

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OBJECTIVE: This study aims to reconstruct a real-world Crash Injury Research and Engineering Network vehicle-to-pedestrian impact to supplement the determination of pedestrian kinematics and injury causation. METHODS: A case involving a 46-year-old male pedestrian with a height of 163 cm and mass of 100 kg that was impacted by a 2019 Dodge Charger Pursuit police cruiser at an approximate velocity of 20.1 m/s was reconstructed. The case vehicle was represented by a rigid shell of a 2019 Dodge Charger vehicle exterior from an open-source database. The case pedestrian was represented by the Global Human Body Models Consortium (GHBMC) 50th percentile male simplified pedestrian human body model. The GHBMC model was isometrically scaled to a height of 163 cm and the external layer of flesh was morphed to a male reference geometry with the same age, height, and body mass index as the case pedestrian. The approximate location and position of the pedestrian at the time of impact was determined from case vehicle dashboard camera images and the pedestrian model was adjusted accordingly. RESULTS: Reconstruction kinematics aligned with proposed CIREN case kinematics. The GHBMC model predicted fractures of the left inferior ischiopubic ramus, superior pubic ramus, ilium, sacral ala, acetabulum, and right ilium. CONCLUSIONS: Finite element reconstructions of real-world pedestrian impacts are useful for analyzing pedestrian kinematics and provide an effective tool for improving pedestrian impact injury analyses.

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OBJECTIVE: While well-protected through a variety of safety countermeasures, motorsports drivers can be exposed to a large variety of crash modes and severities. Computational human body models (HBMs) are currently used to assess occupant safety for the general driving public in production vehicles. The purpose of this study was to incorporate a HBM into a motorsport environment using a simulation-based approach and provide quantitative data on relative risk for on-track motorsport crashes. METHODS: Unlike a traditional automotive seat, the NASCAR driver environment is driver-customized and form-fitting. A multi-step process was developed to integrate the Global Human Body Models Consortium (GHBMC) 50th percentile male simplified occupant into a representative motorsport environment which includes a donned helmet, a 7-point safety belt system, head and neck restraint (HNR), poured-foam seat, steering wheel, and leg enclosure. A series of 45 representative impacts, developed from real-world crash data, of varying severity (10 kph ≤ ΔV ≤ 100 kph) and impact direction (∼290° ≤ PDOF ≤ 20°) were conducted with the GHBMC 50th percentile male simplified occupant (M50-OS v2.2). Kinematic and kinetic data, and a variety of injury criteria, were output from each of the simulations and used to calculate AIS 1+, 2+, and 3+ injury risk. All simulations were conducted in LS-Dyna R. 9.1. RESULTS: Injury risk of the occupant using the previously mentioned injury criteria was calculated for the head, neck, thorax, and lower extremity, and the probability of injury for each region was plotted. Of the simulated impacts, five had a maximum AIS 1+ injury risk >20%, six had a maximum AIS 2+ injury risk >10%, and no cases had a maximum AIS 3+ injury >1%. Overall, injury risk estimates were reasonable compared to on-track data reported from Patalak et al. (2020). CONCLUSIONS: Beyond injury risk, the study is the first of its kind to provide mechanical loading values likely experienced during motorsports crash incidents with crash pulses developed from real-world data. Given the severity of the crash pulses, the simulated environments reinforce the need for the robust safety environment implemented by NASCAR.

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ABSTRACT: Over the last 2 decades, affirmative diagnoses of osteoarthritis (OA) in the United States have tripled due to increasing rates of obesity and an aging population. Hemp-derived cannabidiol (CBD) is the major nontetrahydrocannabinol component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions. Here, we evaluated CBD for its ability to modulate the production of proinflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. Subsequently, the therapeutic potential of both naked and liposomally encapsulated CBD was explored in a 4-week, randomized placebo-controlled, double-blinded study in a spontaneous canine model of OA. In vitro and in mouse models, CBD significantly attenuated the production of proinflammatory cytokines IL-6 and TNF-α while elevating levels of anti-inflammatory IL-10. In the veterinary study, CBD significantly decreased pain and increased mobility in a dose-dependent fashion among animals with an affirmative diagnosis of OA. Liposomal CBD (20 mg/day) was as effective as the highest dose of nonliposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the 4-week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans are warranted.

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Mammalian immune responses are initiated by "danger" signals--immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen-associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel "PAMP" that is not a molecular structure but an antigenic pattern. This pattern--the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II--strongly induces TH 1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl-tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T-helper (TH ) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell-mediated immunity.

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Head injury is a growing concern within contact sports, including American football. Computational tools such as finite element (FE) models provide an avenue for researchers to study, and potentially optimize safety tools, such as helmets. The goal of this study was to develop an accurate representative helmet model that could be used in further study of head injury to mitigate the toll of concussions in contact sports. An FE model of a Schutt Air XP Pro football helmet was developed through three major steps: geometry development, material characterization, and model validation. The fully assembled helmet model was fit onto a Hybrid III dummy head-neck model and National Operating Committee on Standards for Athletic Equipment (NOCSAE) head model and validated through a series of 67 representative impacts similar to those experienced by a football player. The kinematic and kinetic response of the model was compared to the response of the physical experiments, which included force, head linear acceleration, head angular velocity, and carriage acceleration. The outputs between the model and the physical tests were quantitatively evaluated using CORelation and Analysis (CORA), amounting to an overall averaged score of 0.76. The model described in this study has been extensively validated and can function as a building block for innovation in player safety.

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This correction is to add the middle initials of all authors, which were inadvertently omitted from the original article.

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The immune response consists of a finely-tuned program, the activation of which must be coupled with inhibitory mechanisms whenever initiated. This ensures tight control of beneficial anti-pathogen and anti-tumor responses while preserving tissue integrity, promoting tissue repair, and safeguarding against autoimmunity. A cogent example of this binary response is in the mobilization of co-stimulatory and co-inhibitory signaling in regulating the strength and type of a T-cell response. Of particular importance is the costimulatory molecule CD28 which is countered by CTLA-4. While the role of CD28 in the immune response has been thoroughly elucidated, many aspects of CTLA-4 biology remain controversial. The expression of CD28 is largely constrained to constitutive expression in T-cells and as such, teasing out its function has been somewhat simplified by a limited and specific expression profile. The expression of CTLA-4, on the other hand, while reported predominantly in T-cells, has also been described on a diverse repertoire of cells within both lymphoid and myeloid lineages as well as on the surface of tumors. Nonetheless, the function of CTLA-4 has been mostly described within the context of T-cell biology. The focus on T-cell biology may be a direct result of the high degree of amino acid sequence homology and the co-expression pattern of CD28 and CTLA-4, which initially led to the discovery of CTLA-4 as a counter receptor to CD28 (for which a T-cell-activating role had already been described). Furthermore, observations of the outsized role of CTLA-4 in Treg-mediated immune suppression and the striking phenotype of T-cell hyperproliferation and resultant disease in CTLA-4-/- mice contribute to an appropriate T-cell-centric focus in the study of CTLA-4. Complete elucidation of CTLA-4 biology, however, may require a more nuanced understanding of its role in a context other than that of T-cells. This makes particular sense in light of the remarkable, yet limited utility of anti-CTLA-4 antibodies in the treatment of cancers and of CTLA-4-Ig in autoimmune disorders like rheumatoid arthritis. By fully deducing the biology of CTLA-4-regulated immune homeostasis, bottlenecks that hinder the widespread applicability of CTLA-4-based immunotherapies can be resolved.

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NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

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