Research Briefing in 2024

Inflammasomes induce pyroptosis and, through poorly defined mechanisms, promote adaptive immune responses. High-resolution imaging of the explosive morphology of pyroptosis showed that minutes before rupture, gasdermin D instructs the cell to extend filopodia. These structures mark the corpses for recognition by the antigen-sampling receptor CLEC9A on dendritic cells.

Circulating immune stimuli access the joint through fenestrated capillaries that are located at the outer edge of the synovium. This area of vulnerability is policed by interacting macrophages and nociceptor neurons that work together as a functional unit.

Cutaneous T cell lymphoma is a rare, difficult to diagnose malignancy of T cells. Malignant T cells, together with populations of stromal cells and B cells, shape their own tumor niche for improved cancer cell survival in the skin.

We generated a mouse model to investigate the mechanistic basis of inborn errors of immunity caused by heterozygous BCL11B mutation. The BCL11B mutant protein interfered with BCL11A function, impairing T cell and neuronal development. Mutant BCL11B also failed to antagonize TCF1 function, leading to aberrant natural killer cell differentiation in the thymus.

Using temporal and spatial tracking of allergen-specific T cells, we describe the gene regulatory networks that drive T helper 2 cells (T_H2 cells) to develop in response to allergens. Spatial microniches of IL-2 in lymph nodes supported the earliest T_H2 cells, demonstrating lymph node localization is a driver of T_H2 cell initiation.

The Irf8 +32-kb enhancer controls transcriptional autoactivation to generate ‘IRF8 on’ and ‘IRF8 off’ states that define type 1 conventional dendritic cell (cDC1) and cDC2 lineages, respectively. Weak affinity of this enhancer for BATF3–JUNB–IRF8 complexes allows specified cDC2 progenitors to successfully turn off Irf8 transcription. If this enhancer is made stronger, cDC2 commitment and cDC1–cDC2 lineage segregation are compromised.

The G396R coding variant in IGHG1, which encodes membrane-bound IgG1 heavy chain, might have arisen within the Southeast Asian population as a potential evolutionary event on an archaic haplotype background. This variant potentiates immune resilience against various life-threatening organisms, illustrating the interplay of human evolution and immune adaptation.

We integrated single-cell RNA-sequencing data to provide comprehensive profiles of the cellular composition of the tumor microenvironment and identify their underlying genetic determinants across 23 cancer types. We used this resource to delineate the biological mechanisms by which genetic variants shape the cellular composition of the tumor microenvironment.

Tumor cells in emerging cancers modify their gene expression to avoid immune control, a process known as immunoediting. We found that genome-wide gene expression changes in breast tumors after oncogene induction in genetically engineered mice were dominated by the epigenetic repression of innate and adaptive immune genes. Immunoevasion by tumors was reversed by a DNA methyltransferase inhibitor.

Profiling of T cell responses in the lungs of patients with pneumonia revealed that early and persistent enrichment of T cells correlates with survival from SARS-CoV-2 pneumonia. Notably, lung T cells with an interferon-stimulated profile and specific for SARS-CoV-2 structural proteins support survival, whereas those that gain a nuclear factor-κB (NF-κB)-driven inflammatory profile and are directed against nonstructural proteins were associated with poor clinical outcomes.

Patients with Crohn’s disease display an altered serum IgG glycosylation signature that is detectable many years before clinical diagnosis and is associated with increased levels of pathogenic anti-mannan antibodies. The altered IgG glycoforms activate innate immune cells, in a preclinical phase, promoting the transition to intestinal inflammation.

The G protein Gα13 is frequently lost in germinal center (GC) B cell-derived lymphomas. Mice that lack Gα13 exhibit increased proliferation of GC B cells in gut-draining lymph nodes where they go on to develop lymphomas. Dietary glutamine drives the proliferation of mucosal GC B cells that lack Gα13, potentially explaining the gut tropism of these lymphomas.

We constructed a humanized (THX) mouse by grafting non-γ-irradiated, genetically myeloablated immunodeficient mouse neonates with human cord blood CD34⁺ cells, followed by 17β-estradiol hormonal conditioning. THX mice develop a human lymphoid and myeloid immune system, mount mature antibacterial and antiviral neutralizing antibody responses, and are amenable to develop lupus autoimmunity.

We performed transcriptional and chromatin accessibility profiling of T_H17 cells to distinguish the pathways that regulate pathogenic versus non-pathogenic T_H17 cell subsets. We show that T_H17 cell functional heterogeneity is linked to distinct regulatory programs that are shared between T_H17 cells and other CD4⁺ T cell states. BACH2 was identified as a key regulator of T_H17 cell-mediated autoimmunity.

Our study shows that each stimulation experienced by memory B cells is epigenetically recorded in an IRF4-dependent manner, which determines the relative levels of BLIMP1 and BACH2 in B cells, and in turn dictates the likelihood that a memory B cell enters a germinal center or becomes a plasma cell after re-stimulation.

The molecular basis for the efficacy of ZED1227 — a transglutaminase 2 inhibitor — in celiac disease is unknown. We show that orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation at the transcriptome level, and that individuals with high-risk HLA class II celiac disease consistently display a more ‘deteriorated’ molecular phenotype.

IL-1R1 signaling in neural stem cells reduces hippocampal neurogenesis in adult mice, potentially affecting learning and memory. Using a new mouse model, we report that IL-1β drives cognitive impairment after infection with SARS-CoV-2, and that IL-1β-driven cognitive impairment can be prevented by vaccination, even in cases of breakthrough infection.

Improved understanding of CD8⁺ T cell function during HIV infection is vital to designing an HIV cure. We have identified a subset of lymph node CD8⁺ T cells that demonstrate simultaneous stem-like and effector properties and are strongly associated with viral control during SIV and HIV infection.

Variation in inter-individual immune phenotypes can be influenced by both genetics and environmental factors. Using a range of different inbred strains of mice that were kept either indoors or in an outdoor enclosure — ‘rewilded’ — we found that both genetics and environment combine to dictate an individual’s immune profile and outcome to parasitic helminth infections.

Genetic lineage tracing and progenitor and multilineage fate mapping after single hematopoietic stem cell (HSC) transplantations identify two distinct HSC-progenitor trajectories for the replenishment of platelets in mice. These pathways include a slower multilineage pathway and a faster platelet-restricted or biased pathway, initiated by distinct and non-hierarchically related HSCs.