NOD alleles at Idd1 and Idd2 loci drive exocrine pancreatic inflammation.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas.

Highlight of 2023: From fundamental studies to clinical trials, the importance of NK cells against cancer.

In this article for the Highlights of 2023 Series, we discuss how various factors affect the ability of natural killer (NK) cells to fight tumors. For instance, tumor cells can hinder NK cell function by reducing surface protrusions or increasing HLA-E expression via platelets. Lower UTX protein levels in male NK cells also decrease their cytotoxicity compared with females. Fortunately, recent advancements in therapeutic approaches have emerged, including the development of a comprehensive atlas of NK cell heterogeneity within the tumor microenvironment, as well as a trispecific engager molecule that has shown promise in enhancing the anti-tumor functions of NK cells.

Highlight of 2023: Thymic B cells-important players in the establishment of T-cell tolerance.

In this article for the Highlights of 2023 Series, we discuss four recent articles that investigated thymic B cells, in both mice and humans. These studies provide important novel insights into the biology of this unique B-cell population, from their activation and differentiation to their role in promoting the negative selection of thymocytes and the generation of regulatory T cells.

Variations in the germinal center response revealed by genetically diverse mouse strains.

The humoral response is complex and involves multiple cellular populations and signaling pathways. Bacterial and viral infections, as well as immunization regimens, can trigger this type of response, promoting the formation of microanatomical cellular structures called germinal centers (GCs). GCs formed in secondary lymphoid organs support the differentiation of high-affinity plasma cells and memory B cells. There is growing evidence that the quality of the humoral response is influenced by genetic variants. Using 12 genetically divergent mouse strains, we assessed the impact of genetics on GC cellular traits. At steady state, in the spleen, lymph nodes and Peyer's patches, we quantified GC B cells, plasma cells and follicular helper T cells. These traits were also quantified in the spleen of mice following immunization with a foreign antigen, namely, sheep red blood cells, in addition to the number and size of GCs. We observed both strain- and organ-specific variations in cell type abundance, as well as for GC number and size. Moreover, we find that some of these traits are highly heritable. Importantly, the results of this study inform on the impact of genetic diversity in shaping the GC response and identify the traits that are the most impacted by genetic background.

The Idd2 Locus Confers Prominent Resistance to Autoimmune Diabetes.

Type 1 diabetes is an autoimmune disease characterized by pancreatic ß cell destruction. It is a complex genetic trait driven by >30 genetic loci with parallels between humans and mice. The NOD mouse spontaneously develops autoimmune diabetes and is widely used to identify insulin-dependent diabetes (Idd) genetic loci linked to diabetes susceptibility. Although many Idd loci have been extensively studied, the impact of the Idd2 locus on autoimmune diabetes susceptibility remains to be defined. To address this, we generated a NOD congenic mouse bearing B10 resistance alleles on chromosome 9 in a locus coinciding with part of the Idd2 locus and found that NOD.B10-Idd2 congenic mice are highly resistant to diabetes. Bone marrow chimera and adoptive transfer experiments showed that the B10 protective alleles provide resistance in an immune cell-intrinsic manner. Although no T cell-intrinsic differences between NOD and NOD.B10-Idd2 mice were observed, we found that the Idd2 resistance alleles limit the formation of spontaneous and induced germinal centers. Comparison of B cell and dendritic cell transcriptome profiles from NOD and NOD.B10-Idd2 mice reveal that resistance alleles at the Idd2 locus affect the expression of specific MHC molecules, a result confirmed by flow cytometry. Altogether, these data demonstrate that resistance alleles at the Idd2 locus impair germinal center formation and influence MHC expression, both of which likely contribute to reduced diabetes incidence.

Uncoupling of Natural Killer cell functional maturation and cytolytic function in NOD mice.

NK cells are innate immune cells that target infected and tumor cells. Mature NK (mNK) cells undergo functional maturation characterized by four distinct stages, during which they acquire their cytotoxic properties. mNK cells from non-obese diabetic (NOD) mice exhibit a defect in functional maturation and have impaired cytotoxic functions. Hence, we tested whether the impaired cytotoxic function observed in mNK cells from NOD mice can be explained by their defect in functional maturation. By comparing the function of mNK cells from B6, B6g7 and NOD mice, we show that the expression of granzyme B is severely impaired in mNK cells from NOD mice, agreeing with their inability to control tumor growth in vivo. The low level of granzyme B expression in mNK cells from NOD mice is found at all stages of functional maturation and is therefore independent of their functional maturation defect. Consequently, this study demonstrates that phenotypic functional maturation of mNK cells can be uncoupled from the acquisition of cytotoxic functions.

Armstrong strain lymphocytic choriomeningitis virus infection after accidental laboratory exposure.

BACKGROUND: Lymphocytic choriomeningitis virus (LCMV) is a human pathogen naturally present in wild rodents. In addition, LCMV is routinely used in immunology research as a model of viral infection in mice. The Armstrong common laboratory strain and the Clone-13 variant induce acute and chronic infections in mice, respectively. The frequent use of this virus in laboratory settings is associated with a risk of human infection for laboratory personnel. In contrast to LCMV Clone-13, few human laboratory infections with LCMV Armstrong have been reported, leading to a poor understanding of symptoms related to infection with this specific LCMV strain. CASE PRESENTATION: A researcher accidentally infected herself percutaneously with LCMV Armstrong. Symptoms including headaches, dizziness, eye pain and nausea appeared seven days post-exposure and lasted ten days. LCMV-IgM antibodies were detected at 28 days post-infection and IgG seroconversion was observed later. Complete recovery was confirmed three months post exposure. CONCLUSIONS: Research involving live viruses comes with the risk of infection for research personnel. This case is the first reported accidental human infection with LCMV Armstrong. The symptoms differed from reported infections with LCMV Clone-13, by the absence of fever and vomiting, and presence of leg numbness. This report will therefore help clinicians and public health authorities to recognize the symptoms associated with LCMV Armstrong infections and to offer appropriate counselling to individuals who accidentally expose themselves.

OCA-B does not act as a transcriptional coactivator in T cells.

Pou2af1 encodes for OCA-B, a coactivator of OCT-1/2 transcription factors, which plays a key role in B-cell maturation. The function of OCA-B has also been studied in T cells, where T cells from Pou2af1-/- mice have impaired functions, such as cytokine production and T follicular helper (Tfh) differentiation. Arguably, some of these T-cell phenotypes may result from impaired T-B interactions, secondary to the well-documented B-cell defects in Pou2af1-/- mice. Yet, Pou2af1 is actively transcribed in activated T cells, suggesting a T-cell-intrinsic role. To isolate the T-cell-intrinsic impact of Pou2af1, we generated Pou2af1fl/fl mice with specific genetic disruption of Pou2af1 either in all hematopoietic cells or exclusively in T cells. While we confirm that Pou2af1 is expressed in activated T cells, we surprisingly find that T-cell cytokine production is not impaired in Pou2af1-deficient T cells. Moreover, Pou2af1-sufficient and Pou2af1-deficient T cells have comparable transcriptome profiles, arguing against a T-cell-intrinsic role for Pou2af1. In line with these observations, we demonstrate that Tfh maturation is influenced by T-cell-extrinsic deletion of Pou2af1, as observed both in competitive bone marrow chimeras and in Pou2af1fl/fl mice with specific deletion in B cells. Overall, this study provides strong evidence that Pou2af1 does not act as a transcriptional coactivator in T cells, and conclusively demonstrates that loss of OCA-B in B cells indirectly impacts Tfh differentiation, clarifying the role of OCA-B in the immune system.

FLT3 Ligand Is Dispensable for the Final Stage of Type 1 Conventional Dendritic Cell Differentiation.

Conventional dendritic cells (cDCs) are comprised of two major subsets, type 1 cDC (cDC1) and type 2 cDC (cDC2). As each cDC subset differentially influences the nature of immune responses, we sought factors that would allow the manipulation of their relative abundance. Notably, cDC1 are less abundant than cDC2 in both lymphoid and nonlymphoid organs. We demonstrate that this bias is already apparent in bone marrow precommitted precursors. However, comparison of five common inbred strains revealed a disparity in precursor-product relationship, in which mice with fewer precursors to cDC1 had more cDC1. This disparity associated with contrasting variations in CD135 (FLT3) expression on cDC subsets. Hence, we characterized the response to FLT3 ligand during cDC1 and cDC2 lineage differentiation and find that although FLT3 ligand is required throughout cDC2 differentiation, it is surprisingly dispensable during late-stage cDC1 differentiation. Overall, we find that tight regulation of FLT3 ligand levels throughout cDC differentiation dictates the cDC1 to cDC2 ratio in lymphoid organs.

Merocytic Dendritic Cells Compose a Conventional Dendritic Cell Subset with Low Metabolic Activity.

Conventional dendritic cells (cDCs) are arguably the most potent APCs that induce the activation of naive T cells in response to pathogens. In addition, at steady-state, cDCs help maintain immune tolerance. Two subsets of cDCs have been extensively characterized, namely cDC1 and cDC2, each contributing differently to immune responses. Recently, another dendritic cell (DC) subset, termed merocytic DCs (mcDCs), was defined. In contrast to both cDC1 and cDC2, mcDCs reverse T cell anergy, properties that could be exploited to potentiate cancer treatments. Yet, whether mcDCs represent an unconventional DC or a cDC subset remains to be defined. In this article, we further characterize mcDCs and find that they bear true characteristics of cDC subsets. Indeed, as for cDCs, mcDCs express the cDC-restricted transcription factor Zbtb46 and display very potent APC activity. In addition, mcDC population dynamics parallels that of cDC1 and cDC2 in both reconstitution kinetic studies and parabiotic mice. We next investigated their relatedness to cDC1 and cDC2 and demonstrate that mcDCs are not dependent on cDC1-related Irf8 and Batf3 transcription factors, are dependent on Irf4, a cDC2-specific transcription factor, and express a unique transcriptomic signature. Finally, we find that cDC1, cDC2, and mcDCs all present with different metabolic phenotypes, in which mcDCs exhibit the lowest glucose uptake activity and mcDC survival is the least affected by glycolysis inhibition. Defining the properties of mcDCs in mice may help identify a functionally equivalent subset in humans leading to the development of innovative cancer immunotherapies.