People & Ideas
Jen Gommerman is a Canada Research Chair in Tissue Specific Immunity, and a professor and newly appointed chair for the Department of Immunology at the University of Toronto. Her lab is interested in the underlying mechanisms of immune dysregulation in autoimmune diseases such as MS, mucosal immunology, and the role of TNF family members in immune cell biology.
In this issue of JEM, the work of Joachim et al. (2023) on knockin mice with a specific tail mutation in LAT provides valuable insights about cytotoxic CD4+ T cells and human inflammatory diseases.
The authors discuss here B cell activation processes taking place in GALT, repertoire diversification in species like chicken, sheep, or rabbit versus responses to gut flora in humans, both allowing systemic responses against distinct antigens, notably bacterial polysaccharides in humans.
Brief Definitive Reports
IL-22 directly suppresses interferon-γ–induced intestinal and respiratory epithelial cell MHC II. While suppression of IL-22–driven epithelial MHC II may be beneficial in chronic inflammatory conditions, it may increase susceptibility to infection by delaying initiation of appropriate immune responses.
In this study, Rüterbusch et al. report that respiratory exposure to house dust mite allergen or rIL-33 can persistently alter the subsequent functionality of an influenza-specific CD4+ lung TRM population in an antigen-independent, cytokine-dependent manner that impacts disease outcome.
A preclinical mouse model demonstrates that genetic alterations in the blood system characteristic of clonal hematopoiesis (CH) contribute to an aggressive solid tumor phenotype. It further identifies cancer angiogenesis as a potential therapeutic target to mitigate adverse CH effects.
Technical Advances and Resources
Acri and colleagues report transcriptomic responses to tau and elevated tau seeding activity in wild-derived mice relative to C57BL/6J genetic background. This paper creates a rich resource by combining genetics, tau biosensor assays, and transcriptomics.
Joachim et al. deciphered via single-cell transcriptomics and functional genomics the etiopathology of a fast-onset mouse autoimmune and inflammatory disorder due to defective LAT signalosomes. It provides a preclinical model for IgG4-related disease, a human autoimmune and inflammatory condition.
The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling
Sandner et al. uncover a key role for the guanine nucleotide exchange factor Rinl in restraining Tfh differentiation via CD28 signaling in homeostasis, immunization models, virus infection, and aging in mice, and in cultures of human CD4+ T cells.
Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice
Aoun et al. demonstrate that autoreactive B cells, which target collagen type II protein, are present in the natural B cell repertoire of various species. These B cells play a crucial role in tolerizing T cells and suppressing tissue-specific autoimmune inflammation.
This study repurposes metoprolol, a WHO-essential drug, as a potentially safe and effective medication for chimeric antigen receptor (CAR) T–induced human cytokine release syndrome (CRS) and demonstrates that metoprolol relieves CRS via an unexpected mechanism of inhibiting IL-6 translation elongation.
Bhin et al. show that MYC activation drives resistance to mTOR inhibitors and is significantly associated with poor response to mTOR inhibition in breast cancer patients, suggesting the potential of MYC as a biomarker for predicting resistance to mTOR-targeted therapies.
Piersma et al. identify a crucial role for posttranscriptional regulation by HuR in NK cell proliferation. This study reveals that HuR-dependent NK cell expansion is required for control of long-term virus infection and solid tumors without affecting acute infection or tumor metastases.
Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis
Chakraborty et al. demonstrate that a subset of tissue-resident alveolar macrophages shows greater capacity for efferocytosis and prevents hyperinflammation following repeated pathogen challenges. These trained alveolar macrophages exhibit upregulation of the efferocytosis receptor MERTK mediated by the transcription factor KLF4.
Lysosomal cholesterol overload triggers phenotypic changes and profibrotic activation of macrophages around dead hepatocytes containing cholesterol crystals in the development of NASH. Cholesterol excretion from macrophages using β-cyclodextrin polyrotaxane, which is designed to release β-cyclodextrin in lysosomes, alleviates liver fibrosis.
Neuroinflammation is a feature of many neurodegenerative diseases, including Alzheimer's disease. We discovered a new class of molecules with promising potential for clinical application that reduce hallmarks of neuroinflammation by inhibiting the PU.1 transcription factor, a master regulator of inflammation.
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition
In this study, we have discovered that hemifacial myohyperplasia results from a somatic gain-of-function mutation in PI3KCA. Using a new mouse model, we investigated the underlying mechanisms and demonstrated that alpelisib, a pharmacological inhibitor, significantly enhances both the preclinical model and patients.
Correction: Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice