Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection.

CD4+ T cell-derived interleukin 21 (IL-21) sustains CD8+ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21+CD4+ T cells during LCMV clone 13 infection. CD4+ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6+ Th1 cells, Cxcr5+ Tfh cells, and a previously unrecognized Slamf6+ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8+ T cell responses and viral control. Thus, strategies that bolster IL-21+Tfh cell responses may prove effective in enhancing CD8+ T cell-mediated immunity.

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups.

BACKGROUND AND OBJECTIVES: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti-HBc) prevents transfusion-transmitted HBV infection but can lead to significant donor loss. As isolated anti-HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti-HBc testing and the representation of rare blood groups in anti-HBc-positive donors. MATERIALS AND METHODS: Three hundred ninety-seven HBV surface antigen-negative and anti-HBc initially reactive blood donor samples were tested by five different anti-HBc assays. RESULTS: Eighty percentage of samples reactive in Architect anti-HBc assay were positive by the Murex assay and anti-HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty-eight percentage of anti-HBc-positive donors identified as minority ethnic groups compared with 11% representation in anti-HBc-negative donors (p < 0.0001); the frequency of the Ro blood group in anti-HBc-positive donors was 18 times higher in non-white ethnic groups. CONCLUSION: Using two anti-HBc assays effectively enabled the identification of HBV-exposed and potentially infectious donors, their deferral and potential clinical follow-up. However, the exclusion of confirmed anti-HBc-positive donors will still impact the supply of rare blood such as Ro.

Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.

BACKGROUND: Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. METHODS: Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. RESULTS: Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. CONCLUSIONS: In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.

Improving dementia care: insights from audit and feedback in interdisciplinary primary care sites.

BACKGROUND: Many primary care sites have implemented models to improve detection, diagnosis, and management of dementia, as per Canadian guidelines. The aim of this study is to describe the responses of clinicians, managers, and staff of sites that have implemented these models when presented with audit results, their insights on the factors that explain their results, their proposed solutions for improvement and how these align to one another. METHODS: One audit and feedback cycle was carried out in eight purposefully sampled sites in Ontario, Canada, that had previously implemented dementia care models. Audit consisted of a) chart review to assess quality of dementia care indicators, b) questionnaire to assess the physicians' knowledge, attitudes and practice toward dementia care, and c) semi-structured interviews to understand barriers and facilitators to implementing these models. Feedback was given to clinicians, managers, and staff in the form of graphic and oral presentations, followed by eight focus groups (one per site). Discussions revolved around: what audit results elicited more discussion from the participants, 2) their insights on the factors that explain their audit results, and 3) solutions they propose to improve dementia care. Deductive content and inductive thematic analyses, grounded in causal pathways models' theory was performed. FINDINGS: The audit and feedback process allowed the 63 participants to discuss many audit results and share their insights on a) organizational factors (lack of human resources, the importance of organized links with community services, clear roles and support from external memory clinics) and b) clinician factors (perceived competency practice and attitudes on dementia care), that could explain their audit results. Participants also provided solutions to improve dementia care in primary care (financial incentives, having clear pathways, adding tools to improve chart documentation, establish training on dementia care, and the possibility of benchmarking with other institutions). Proposed solutions were well aligned with their insights and further nuanced according to contextual details. CONCLUSIONS: This study provides valuable information on solutions proposed by primary care clinicians, managers, and staff to improve dementia care in primary care. The solutions are grounded in clinical experience and will inform ongoing and future dementia strategies.

Asthma medication usage is significantly reduced following bariatric surgery.

INTRODUCTION: Asthma is an important healthcare problem affecting millions in the United States. Additionally, a large proportion of patients with asthma suffer from obesity. These patients exhibit poor asthma control and reduced therapy response, increasing utilization of healthcare resources. Pulmonary symptoms improve after bariatric surgery (BS), and we hypothesized that asthma medication usage would decrease following BS. METHODS: A retrospective data analysis was performed in adult patients from a single institution's database. Patients with obesity using at least one asthma medication pre-operatively who underwent BS were studied for up to 3-years post-operation. Poisson generalized linear mixed models for repeated measures were used to evaluate the effects of time and procedure type on the number of asthma medication. RESULTS: Bariatric patients with at least one prescribed asthma medication (mean 1.4 ± 0.6) were included (n = 751). The mean age at time of operation was 46.8 ± 11.6 years, mean weight was 295.9 ± 57 lbs, and mean body mass index (BMI) was 49 ± 8.2 kg/m2; 87.7% were female, 33.4% had diabetes, 44.2% used gastroesophageal reflux disease (GERD) medication, and 64.4% used hypertension medication. The most common procedure was Roux-en-Y gastric bypass (79%), followed by sleeve gastrectomy (10.7%), adjustable gastric banding (8.1%), and duodenal switch (2.3%). The mean number of prescribed asthma medications among all procedures decreased by 27% at 30 days post-operation (p < 0.0001), 37% at 6 months (p < 0.0001), 44% at 1 year (p < 0.0001), and 46% at 3 years (p < 0.0001) after adjusting for risk factors. No significant differences in medication use over time between procedure types were observed. In the adjusted analysis, the mean number of asthma medications was 12% higher in patients using at least one GERD medication (p = 0.015) and 8% higher with 10-unit increase in pre-operative BMI (p = 0.006). CONCLUSION: BS significantly decreases asthma medication use starting 30 days post-operation with a sustained reduction for up to 3 years.

Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications.

BACKGROUND: Eosinophils are prominent in some patients with asthma and are increased in the submucosa in a subgroup of obese patients with asthma (OAs). Surfactant protein A (SP-A) modulates host responses to infectious and environmental insults. OBJECTIVE: We sought to determine whether SP-A levels are altered in OAs compared with a control group and to determine the implications of these alterations in SP-A levels in asthmatic patients. METHODS: Bronchoalveolar lavage fluid from 23 lean, 12 overweight, and 20 obese subjects were examined for SP-A. Mouse tracheal epithelial cells grown at an air-liquid interface were used for mechanistic studies. SP-A-/- mice were challenged in allergen models, and exogenous SP-A therapy was given after the last challenge. Eosinophils were visualized and quantitated in lung parenchyma by means of immunostaining. RESULTS: Significantly less SP-A (P = .002) was detected in samples from OAs compared with those from control subjects. A univariable regression model found SP-A levels were significantly negatively correlated with body mass index (r = -0.33, P = .014), whereas multivariable modeling demonstrated that the correlation depended both on asthma status (P = .017) and the interaction of asthma and body mass index (P = .008). Addition of exogenous TNF-α to mouse tracheal epithelial cells was sufficient to attenuate SP-A and eotaxin secretion. Allergen-challenged SP-A-/- mice that received SP-A therapy had significantly less tissue eosinophilia compared with mice receiving vehicle. CONCLUSIONS: SP-A functions as an important mediator in resolving tissue and lavage fluid eosinophilia in allergic mouse models. Decreased levels of SP-A in OAs, which could be due to increased local TNF-α levels, might lead to impaired eosinophil resolution and could contribute to the eosinophilic asthma phenotype.

A Context-Dependent Role for IL-21 in Modulating the Differentiation, Distribution, and Abundance of Effector and Memory CD8 T Cell Subsets.

The activation of naive CD8 T cells typically results in the formation of effector cells (TE) as well as phenotypically distinct memory cells that are retained over time. Memory CD8 T cells can be further subdivided into central memory, effector memory (TEM), and tissue-resident memory (TRM) subsets, which cooperate to confer immunological protection. Using mixed bone marrow chimeras and adoptive transfer studies in which CD8 T cells either do or do not express IL-21R, we discovered that under homeostatic or lymphopenic conditions IL-21 acts directly on CD8 T cells to favor the accumulation of TE/TEM populations. The inability to perceive IL-21 signals under competitive conditions also resulted in lower levels of TRM phenotype cells and reduced expression of granzyme B in the small intestine. IL-21 differentially promoted the expression of the chemokine receptor CX3CR1 and the integrin α4ß7 on CD8 T cells primed in vitro and on circulating CD8 T cells in the mixed bone marrow chimeras. The requirement for IL-21 to establish CD8 TE/TEM and TRM subsets was overcome by acute lymphocytic choriomeningitis virus infection; nevertheless, memory virus-specific CD8 T cells remained dependent on IL-21 for optimal accumulation in lymphopenic environments. Overall, this study reveals a context-dependent role for IL-21 in sustaining effector phenotype CD8 T cells and influencing their migratory properties, accumulation, and functions.

Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

Hyaluronan (HA), a major component of the extracellular matrix, is secreted by airway structural cells. Airway fibroblasts in allergic asthma secrete elevated levels of HA in association with increased HA synthase 2 (HAS2) expression. Thus, we hypothesized that HA accumulation in the airway wall may contribute to airway remodeling and hyperresponsiveness in allergic airways disease. To examine this hypothesis, transgenic mice in which the α-smooth muscle actin (α-SMA) promoter drives HAS2 expression were generated. Mixed male and female α-SMA-HAS2 mice (HAS2+ mice, n = 16; HAS2- mice, n = 13) were sensitized via intraperitoneal injection and then chronically challenged with aerosolized ovalbumin (OVA) for 6 weeks. To test airway responsiveness, increasing doses of methacholine were delivered intravenously and airway resistance was measured using the forced oscillation technique. HA, cytokines, and cell types were analyzed in bronchoalveolar lavage fluid, serum, and whole lung homogenates. Lung sections were stained using antibodies specific for HA-binding protein (HABP) and α-SMA, as well as Masson's trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, α-SMA, and collagen deposition in OVA-challenged α-SMA-HAS2+ mice compared with α-SMA-HAS2- mice. Unexpectedly, OVA-challenged α-SMA-HAS2+ mice displayed significantly reduced airway responsiveness to methacholine compared with similarly treated α-SMA-HAS2- mice. The total numbers of inflammatory cell types in the bronchoalveolar lavage fluid did not differ significantly between OVA-challenged α-SMA-HAS2+ mice and α-SMA-HAS2- mice. We conclude that allergen-challenged mice that overexpress HAS2 in myofibroblasts and smooth muscle cells develop increased airway fibrosis, which lessens airway hyperresponsiveness to bronchoconstrictors.

A Heterotopic Xenograft Model of Human Airways for Investigating Fibrosis in Asthma.

Limited in vivo models exist to investigate the lung airway epithelial role in repair, regeneration, and pathology of chronic lung diseases. Herein, we introduce a novel animal model in asthma-a xenograft system integrating a differentiating human asthmatic airway epithelium with an actively remodeling rodent mesenchyme in an immunocompromised murine host. Human asthmatic and nonasthmatic airway epithelial cells were seeded into decellularized rat tracheas. Tracheas were ligated to a sterile cassette and implanted subcutaneously in the flanks of nude mice. Grafts were harvested at 2, 4, or 6 weeks for tissue histology, fibrillar collagen, and transforming growth factor-ß activation analysis. We compared immunostaining in these xenografts to human lungs. Grafted epithelial cells generated a differentiated epithelium containing basal, ciliated, and mucus-expressing cells. By 4 weeks postengraftment, asthmatic epithelia showed decreased numbers of ciliated cells and decreased E-cadherin expression compared with nonasthmatic grafts, similar to human lungs. Grafts seeded with asthmatic epithelial cells had three times more fibrillar collagen and induction of transforming growth factor-ß isoforms at 6 weeks postengraftment compared with nonasthmatic grafts. Asthmatic epithelium alone is sufficient to drive aberrant mesenchymal remodeling with fibrillar collagen deposition in asthmatic xenografts. Moreover, this xenograft system represents an advance over current asthma models in that it permits direct assessment of the epithelial-mesenchymal trophic unit.

A novel role for primary cilia in airway remodeling.

Primary cilia (PC) are solitary cellular organelles that play critical roles in development, homeostasis, and disease pathogenesis by modulating key signaling pathways such as Sonic Hedgehog and calcium flux. The antenna-like shape of PC enables them also to facilitate sensing of extracellular and mechanical stimuli into the cell, and a critical role for PC has been described for mesenchymal cells such as chondrocytes. However, nothing is known about the role of PC in airway smooth muscle cells (ASMCs) in the context of airway remodeling. We hypothesized that PC on ASMCs mediate cell contraction and are thus integral in the remodeling process. We found that PC are expressed on ASMCs in asthmatic lungs. Using pharmacological and genetic methods, we demonstrated that PC are necessary for ASMC contraction in a collagen gel three-dimensional model both in the absence of external stimulus and in response to the extracellular component hyaluronan. Mechanistically, we demonstrate that the effect of PC on ASMC contraction is, to a small extent, due to their effect on Sonic Hedgehog signaling and, to a larger extent, due to their effect on calcium influx and membrane depolarization. In conclusion, PC are necessary for the development of airway remodeling by mediating calcium flux and Sonic Hedgehog signaling.

Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.

Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.

Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-ß1 in airway fibroblasts in asthma.

Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)- and transforming growth factor (TGF)-ß1-dependent manner in human asthma as compared to healthy controls. Fibroblasts were cultured from endobronchial biopsies in 14 subjects with mild asthma and 13 normal controls that underwent bronchoscopy. Airway fibroblasts were treated with various mediators including IL-13 and specific MMP-inhibitors. IL-13 significantly stimulated collagen type-1 production in asthma compared to normal controls. Inhibitors of MMP-2 significantly attenuated collagen production in asthma but had no effect in normal controls. IL-13 significantly increased total and active forms of TGF-ß1, and this activation was blocked using an MMP-2 inhibitor. IL-13 activated endogenous MMP-2 in asthma patients as compared to normal controls. In an ex vivo model, IL-13 potentiates airway remodelling through a mechanism involving TGF-ß1 and MMP-2. These effects provide insights into the mechanism involved in IL-13-directed airway remodelling in asthma.

SHP-1 as a critical regulator of Mycoplasma pneumoniae-induced inflammation in human asthmatic airway epithelial cells.

Asthma is a chronic inflammatory disease in which airway epithelial cells are the first line of defense against exposure of the airway to infectious agents. Src homology protein (SHP)-1, a protein tyrosine phosphatase, is a negative regulator of signaling pathways that are critical to the development of asthma and host defense. We hypothesize that SHP-1 function is defective in asthma, contributing to the increased inflammatory response induced by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. M. pneumoniae significantly activated SHP-1 in airway epithelial cells collected from nonasthmatic subjects by bronchoscopy with airway brushing but not in cells from asthmatic subjects. In asthmatic airway epithelial cells, M. pneumoniae induced significant PI3K/Akt phosphorylation, NF-κB activation, and IL-8 production compared with nonasthmatic cells, which were reversed by SHP-1 overexpression. Conversely, SHP-1 knockdown significantly increased IL-8 production and PI3K/Akt and NF-κB activation in the setting of M. pneumoniae infection in nonasthmatic cells, but it did not exacerbate these three parameters already activated in asthmatic cells. Thus, SHP-1 plays a critical role in abrogating M. pneumoniae-induced IL-8 production in nonasthmatic airway epithelial cells through inhibition of PI3K/Akt and NF-κB activity, but it is defective in asthma, resulting in an enhanced inflammatory response to infection.

Utility of the theory of planned behavior to predict nursing staff blood pressure monitoring behaviours.

AIMS AND OBJECTIVES: To evaluate constructs from the theory of planned behavior (TPB, Ajzen 2002) - attitudes, sense of control, subjective norms and intentions - as predictors of accuracy in blood pressure monitoring. BACKGROUND: Despite numerous initiatives aimed at teaching blood pressure measurement techniques, many healthcare providers measure blood pressures incorrectly. DESIGN: Descriptive, cohort design. METHODS: Medical assistants and licensed practical nurses were asked to complete a questionnaire on TPB variables. These nursing staff's patients had their blood pressures measured and completed a survey about techniques used to measure their blood pressure. We correlated nursing staff's responses on the TBP questionnaire with their intention to measure an accurate blood pressure and with the difference between their actual blood pressure measurement and a second measurement taken by a researcher immediately after the clinic visit. Patients' perceptions of MAs' and LPNs' blood pressure measurement techniques were examined descriptively. RESULTS: Perceived control and social norm predicted intention to measure an accurate blood pressure, with a negative relationship between knowledge and intention. Consistent with the TPB, intention was the only significant predictor of blood pressure measurement accuracy. CONCLUSIONS: Theory of planned behavior constructs predicted the healthcare providers' intention to measure blood pressure accurately and intention predicted the actual accuracy of systolic blood pressure measurement. However, participants' knowledge about blood pressure measurement had an unexpected negative relationship with their intentions. RELEVANCE TO CLINICAL PRACTICE: These findings have important implications for nursing education departments and organisations which traditionally invest significant time and effort in annual competency training focused on knowledge enhancement by staff. This study suggests that a better strategy might involve efforts to enhance providers' intention to change, particularly by changing social norms or increasing perceived control of the behaviour by nursing staff.

Short-term cardiovascular events after bariatric surgery in patients with metabolic syndrome.

BACKGROUND: Patients with metabolic syndrome (MetS) are at increased risk of developing cardiovascular disease along with other adverse events after bariatric surgery. OBJECTIVES: The incidence of short-term major adverse cardiovascular events (MACE) in patients with MetS undergoing bariatric surgery is not well characterized. SETTING: Accredited bariatric surgery centers in the United States and Canada. METHODS: A total of 760,076 patients aged ≥18 years with body mass index ≥35 kg/m2 who underwent primary bariatric surgery between 2015 and 2018 were included. Patients with both diabetes and hypertension were described as the MetS cohort. Patient characteristics, operative technique, and 30-day outcomes were compared. The primary outcome was incidence of MACE, a composite of myocardial infarction, stroke, and all-cause mortality. Unadjusted and multivariable logistic regression analyses were performed and included an interaction between MetS and hyperlipidemia (HLD). RESULTS: Of the 577,882 patients included, 111,128 (19.2%) exhibited MetS. Patients with MetS more frequently experienced MACE compared with patients without MetS (.3% versus .1%; P < .001). The odds of MACE were greater for patients with MetS versus Non-MetS (odds ratio [OR] 2.87; 95% CI, 2.49-3.32) in the unadjusted analysis. MetS without HLD, MetS with HLD, and Non-MetS with HLD are significantly associated with MACE when compared with those with non-MetS without HLD. CONCLUSIONS: Patients with MetS have an increased frequency of cardiac events following bariatric surgery. Future studies should determine if optimization of 1 or more components of MetS or other related co-morbidities reduces the cardiovascular risk for patients.

Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 - CX3CR1 + effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited. However, the precise cues and mechanisms directing the formation and maintenance of exhausted effector-like are incompletely understood. Using genetic mouse models challenged with LCMV Clone 13 or syngeneic tumors, we show that the expression of a transcriptional repressor, growth factor independent 1 (Gfi1) is dynamically regulated in exhausted CD8 T cells, which in turn regulates the formation of exhausted effector-like cells. Gfi1 deletion in T cells dysregulates the chromatin accessibility and transcriptomic programs associated with the differentiation of LCMV Clone 13-specific CD8 T cell exhaustion, preventing the formation of effector-like and terminally exhausted cells while maintaining progenitors and a newly identified Ly108 + CX3CR1 + state. These Ly108 + CX3CR1 + cells have a distinct chromatin profile and may represent an alternative target for therapeutic interventions to combat chronic infections and cancer. In sum, we show that Gfi1 is a critical regulator of the formation of exhausted effector-like cells.