Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse.

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models.

gain-of-function mutation drives cell-autonomous accumulation of PD-1 ICOS activated T cells, T-follicular, T-regulatory and T-follicular regulatory cells.

Introduction: Germline CARD11 gain-of-function (GOF) mutations cause B cell Expansion with NF-κB and T cell Anergy (BENTA) disease, whilst somatic GOF CARD11 mutations recur in diffuse large B cell lymphoma (DLBCL) and in up to 30% of the peripheral T cell lymphomas (PTCL) adult T cell leukemia/lymphoma (ATL), cutaneous T cell lymphoma (CTCL) and Sezary Syndrome. Despite their frequent acquisition by PTCL, the T cell-intrinsic effects of CARD11 GOF mutations are poorly understood.

Methods: Here, we studied B and T lymphocytes in mice with a germline Nethyl-N-nitrosourea (ENU)-induced Card11 mutation identical to a mutation identified in DLBCL and modifying a conserved region of the CARD11 coiled-coil domain recurrently mutated in DLBCL and PTCL.

Tracking the clonal dynamics of SARS-CoV-2-specific T cells in children and adults with mild/asymptomatic COVID-19.

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion.

PI3K Isoforms in B Cells.

Phosphatidylinositol-3-kinases (PI3K) control many aspects of cellular activation and differentiation and play an important role in B cells biology. Three different classes of PI3K have been described, all of which are expressed in B cells. However, it is the class IA PI3Ks, and the p110δ catalytic subunit in particular, which seem to play the most critical role in B cells.

Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.

For whom the B cells toll.

Researchers have identified a new monogenic form of systemic lupus erythematosus caused by mutations that result in increased Toll-like receptor 7 (TLR7) signaling.

STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis.

Background: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown.

The role of dysregulated PI3Kdelta signaling in human autoimmunity.

Better treatment of autoimmune diseases requires an improved understanding of the cellular and molecular mechanisms that lead to the breakdown of immune tolerance. The discovery of individuals with germline mutations in PIK3CD (which encodes the p110δ catalytic subunit of PI3K) has revealed the importance of regulated PI3Kδ activity to maintain tolerance. These patients display a range of symptoms including both immunodeficiency and autoimmunity.

Phosphatidylinositol 3-kinase signaling and immune regulation: insights into disease pathogenesis and clinical implications.

Introduction: Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that plays a fundamental role in cell survival, metabolism, proliferation and differentiation. Thus, balanced PI3K signalling is critical for multiple aspects of human health. The discovery that germline variants in genes in the PI3K pathway caused inborn errors of immunity highlighted the non-redundant role of these signalling proteins in the human immune system.

B cells: we need them now more than ever.

The humoral immune response, that is, the production of antibodies by B cells, is a critical component of immunity to infection and underlies the protection provided by the majority of successful vaccines. This Special Feature explores some of the latest advances in understanding B cell activation and differentiation, as well as how these processes can go wrong in disease.

Molecular and cellular mechanisms underlying defective antibody responses.

Primary immune deficiency is caused by genetic mutations that result in immune dysfunction and subsequent susceptibility to infection. Over the last decade there has been a dramatic increase in the number of genetically defined causes of immune deficiency including those which affect B-cell function. This has not only identified critical nonredundant pathways that control the generation of protective antibody responses but also revealed that immunodeficiency and autoimmunity are often closely linked.

NK Cells Regulate CD8 T Cell Mediated Autoimmunity.

Elucidating key factors that regulate immune-mediated pathology is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8 T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8 T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV.

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production.

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies.

Immune Dysregulation and Disease Pathogenesis due to Activating Mutations in PIK3CD-the Goldilocks' Effect.

"This porridge is too hot!" she exclaimed. So, she tasted the porridge from the second bowl. "This porridge is too cold," she said.

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells.

Germline-activating mutations in compromise B cell development and function.

Gain-of-function (GOF) mutations in , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery.