Pivotal role of exogenous pyruvate in human natural killer cell metabolism.

Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability.

Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells.

Mendelian Causes of Autoimmunity: the Lupus Phenotype.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci.

Phenotypic Variability in PRKCD: a Review of the Literature.

Purpose: Protein kinase C δ (PKCδ) deficiency is a rare genetic disorder identified as a monogenic cause of systemic lupus erythematosus in 2013. Since the first cases were described, the phenotype has expanded to include children presenting with autoimmune lymphoproliferative syndrome-related syndromes and infection susceptibility similar to chronic granulomatous disease or combined immunodeficiency. We review the current published data regarding the pathophysiology, clinical presentation, investigation and management of PKCδ deficiency.

Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells.

EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions.

Polyclonal expansion of TCR Vbeta 21.3 CD4 and CD8 T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases.

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations.

Zeb1 represses TCR signaling, promotes the proliferation of T cell progenitors and is essential for NK1.1 T cell development.

T cell development proceeds under the influence of a network of transcription factors (TFs). The precise role of Zeb1, a member of this network, remains unclear. Here, we report that Zeb1 expression is induced early during T cell development in CD4CD8 double-negative (DN) stage 2 (DN2).

Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts.

Background: Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE.

Monogenic lupus: Dissecting heterogeneity.

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus.

Comparison of RT-qPCR and Nanostring in the measurement of blood interferon response for the diagnosis of type I interferonopathies.

Type I interferonopathies are characterized by an increase of circulating type I interferon (IFN) concentration. Type I interferonopathies refer to rare Mendelian genetic disorders such as Aicardi-Goutières Syndrome (AGS) as well as more frequent and polygenic auto-immune diseases like systemic lupus erythematosus (SLE). Yet, detection of type I IFN in these patients remains challenging as its amount is usually very low in patients' sera.

Deletion of Inflammasome Components Is Not Sufficient To Prevent Fatal Inflammation in Models of Familial Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition that occurs in patients with genetic defects of cytotoxicity (familial HLH [FHL]) or secondary to other immunological disorders such as juvenile idiopathic arthritis. HLH is characterized by elevated levels of serum IL-18 and other cytokines. Moreover, a novel clinical entity has been recently identified in which constitutive NLRC4 inflammasome activation leads to severe HLH.

Antigen-Induced but Not Innate Memory CD8 T Cells Express NKG2D and Are Recruited to the Lung Parenchyma upon Viral Infection.

The pool of memory-phenotype CD8 T cells is composed of Ag-induced (AI) and cytokine-induced innate (IN) cells. IN cells have been described as having properties similar to those of AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished in mice from naturally generated IN memory cells by surface expression of NKG2D.

T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1.

T-bet and Eomes are T-box transcription factors that drive the differentiation and function of cytotoxic lymphocytes such as NK cells. Their DNA-binding domains are highly similar, suggesting redundant transcriptional activity. However, while these transcription factors have different patterns of expression, the phenotype of loss-of-function mouse models suggests that they play distinct roles in the development of NK cells and other innate lymphoid cells (ILCs).

Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection.

Natural killer (NK) cell maturation is a tightly controlled process that endows NK cells with functional competence and the capacity to recognize target cells. Here, we found that the transcription factor (TF) Zeb2 was the most highly induced TF during NK cell maturation. Zeb2 is known to control epithelial to mesenchymal transition, but its role in immune cells is mostly undefined.

Inherited anomalies of innate immune receptors in pediatric-onset inflammatory diseases.

Pattern-recognition receptors (PRRs) can detect various pathogen-associated molecular patterns such as carbohydrates, nucleic acids or bacterial peptides and play a major role in both innate and adaptive immunity. In physiological conditions, the engagement of PRRs triggers the production of proinflammatory cytokines and promotes pathogen destruction. Inappropriate stimulation or defective regulation of PRR has been recently evidenced in several inherited inflammatory disorders.