In this issue of JEM, Qiu et al. (2023. J. Exp. Med. https://doi.org/10.1084/jem.20210923) show that retinoic acid signaling during priming in the mesenteric lymph node licenses CD8+ T cells to develop into small intestinal tissue-resident memory cells, a finding that provides key insights into tissue-specific vaccination strategies.

Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor involved in regulation of immune cell activation and differentiation. Recent discoveries highlight the role of germline activating STAT3 mutations in inborn errors of immunity characterized by early-onset multi-organ autoimmunity and lymphoproliferation. Much progress has been made in defining the clinical spectrum of STAT3 GOF disease and unraveling the molecular and cellular mechanisms underlying this disease. In this review, we summarize our current understanding of the disease and discuss the clinical phenotype, diagnostic approach, cellular and molecular effects of STAT3 GOF mutations and therapeutic concepts for these patients.

The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathways architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.

BACKGROUND: Information regarding the prevalence of infectious diseases (IDs) in child and adolescent refugees in Europe is scarce. Here, we evaluate a standardized ID screening protocol in a cohort of unaccompanied refugee minors (URMs) in a municipal region of southwest Germany. METHODS AND FINDINGS: From January 2016 to December 2017, we employed a structured questionnaire to screen a cohort of 890 URMs. Collecting sociodemographic information and medical history, we also performed a standardized diagnostics panel, including complete blood count, urine status, microbial stool testing, tuberculosis (TB) screening, and serologies for hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The mean age was 16.2 years; 94.0% were male, and 93.6% originated from an African country. The most common health complaints were dental problems (66.0%). The single most frequent ID was scabies (14.2%). Of the 776 URMs originating from high-prevalence countries, 7.7% and 0.4% tested positive for HBV and HIV, respectively. Nineteen pathogens were detected in a total of 119 stool samples (16.0% positivity), with intestinal schistosomiasis being the most frequent pathogen (6.7%). Blood eosinophilia proved to be a nonspecific criterion for the detection of parasitic infections. Active pulmonary TB was identified in 1.7% of URMs screened. Of note, clinical warning symptoms (fever, cough >2 weeks, and weight loss) were insensitive parameters for the identification of patients with active TB. Study limitations include the possibility of an incomplete eosinophilia workup (as no parasite serologies or malaria diagnostics were performed), as well as the inherent selection bias in our cohort because refugee populations differ across Europe. CONCLUSIONS: Our study found that standardized ID screening in a URM cohort was practicable and helped collection of relevant patient data in a thorough and time-effective manner. However, screening practices need to be ameliorated, especially in relation to testing for parasitic infections. Most importantly, we found that only a minority of infections were able to be detected clinically. This underscores the importance of active surveillance of IDs among refugees.

Tissue-resident memory T cells (T_RM cells) provide protective immunity, but the contributions of specific tissue environments to T_RM cell differentiation and homeostasis are not well understood. In the present study, the diversity of gene expression and genome accessibility by mouse CD8⁺ T_RM cells from distinct organs that responded to viral infection revealed both shared and tissue-specific transcriptional and epigenetic signatures. T_RM cells in the intestine and salivary glands expressed transforming growth factor (TGF)-β-induced genes and were maintained by ongoing TGF-β signaling, whereas those in the fat, kidney and liver were not. Constructing transcriptional-regulatory networks identified the transcriptional repressor Hic1 as a critical regulator of T_RM cell differentiation in the small intestine and showed that Hic1 overexpression enhanced T_RM cell differentiation and protection from infection. Provision of a framework for understanding how CD8⁺ T_RM cells adapt to distinct tissue environments, and identification of tissue-specific transcriptional regulators mediating these adaptations, inform strategies to boost protective memory responses at sites most vulnerable to infection.

Data on therapy of COVID-19 in immunocompetent and immunosuppressed children are scarce. We aimed to explore management strategies of pediatric rheumatologists. All subscribers to international Pediatric Rheumatology Bulletin Board were invited to take part in an online survey on therapeutic approaches to COVID-19 in healthy children and children with autoimmune/inflammatory diseases (AID). Off-label therapies would be considered by 90.3% of the 93 participating respondents. In stable patients with COVID-19 on oxygen supply (stage I), use of remdesivir (48.3%), azithromycin (26.6%), oral corticosteroids (25.4%) and/or hydroxychloroquine (21.9%) would be recommended. In case of early signs of cytokine storm (stage II) or in critically ill patients (stage III) (a) anakinra (79.5% stage II; 83.6% stage III) or tocilizumab (58.0% and 87.0%, respectively); (b) corticosteroids (oral 67.2% stage II, intravenously 81.7% stage III); (c) intravenous immunoglobulins (both stages 56.5%); or (d) remdesivir (both stages 46.7%) were considered. In AID, > 94.2% of the respondents would not support a preventive adaptation of the immunomodulating therapy. In case of mild COVID-19, more than 50% of the respondents would continue pre-existing treatment with immunoglobulins (100%), hydroxychloroquine (94.2%), anakinra (79.2%) or canakinumab (72.5%), or tocilizumab (69.8%). Long-term corticosteroids would be reduced by 26.9% (< = 2 mg/kg/d) and 50.0% (> 2 mg/kg/day), respectively, with only 5.8% of respondents voting to discontinue the therapy. Conversely, more than 75% of respondents would refrain from administering cyclophosphamide and anti-CD20-antibodies. As evidence on management of pediatric COVID-19 is incomplete, continuous and critical expert opinion and knowledge exchange is helpful.

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.

Timely detection of portal hypertension as a manifestation in a subgroup of patients with common variable immunodeficiency (CVID) represents a challenge since it is usually not associated with liver cirrhosis. To identify relevant markers for portal hypertension, we evaluated clinical history, laboratory parameters, and abdominal ultrasound including liver elastography and biomarkers of extracellular matrix formation. Twenty seven (6%) of 479 CVID patients presented with clinically significant portal hypertension as defined by either the presence of esophageal varices or ascites. This manifestation occurred late during the course of the disease (11.8 years after first diagnosis of CVID) and was typically part of a multiorgan disease and associated with a high mortality (11/27 patients died during follow up). The strongest association with portal hypertension was found for splenomegaly with a longitudinal diameter of > 16 cm. Similarly, most patients presented with a liver stiffness measurement (LSM) of above 6.5 kPa, and a LSM above 20 kPa was always indicative of manifest portal hypertension. Additionally, many laboratory parameters including Pro-C4 were significantly altered in patients with portal hypertension without clearly increasing the discriminatory power to detect non-cirrhotic portal hypertension in CVID. Our data suggest that a spleen size above 16 cm and an elevated liver stiffness above 6.5 kPa should prompt further evaluation of portal hypertension and its sequelae, but earlier and better liquid biomarkers of this serious secondary complication in CVID are needed.

After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8⁺ tissue-resident memory T cells (T_RM), the developmental origins and transcriptional regulation of CD4⁺ T_RM remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profiles of CD4⁺ T_RM in the small intestine (SI) responding to acute viral infection, revealing a shared gene expression program and chromatin accessibility profile with circulating T_H1 and the progressive acquisition of a mature T_RM program. Single-cell RNA sequencing identified heterogeneity among established CD4⁺ T_RM, which were predominantly located in the lamina propria, and revealed a population of cells that coexpressed both effector- and memory-associated genes, including the transcriptional regulators Blimp1, Id2, and Bcl6. T_H1-associated Blimp1 and Id2 and T_FH-associated Bcl6 were required for early T_RM formation and development of a mature T_RM population in the SI. These results demonstrate a developmental relationship between T_H1 effector cells and the establishment of early T_RM, as well as highlighted differences in CD4⁺ versus CD8⁺ T_RM populations, providing insights into the mechanisms underlying the origins, differentiation, and persistence of CD4⁺ T_RM in response to viral infection.

Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.