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Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor β repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I– and class II–restricted SARS-CoV-2–specific responses and also identified several HLA allele–clonotype motif associations in patients with COVID-19, including a subcohort of anti–type 1 interferon (IFN-1)-positive patients. Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2–specific clonotypes targeted a broad range of HLA class I– and class II–restricted epitopes across the viral proteome. The presence of anti–IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2–specific clonotypes in patients with IEIs, including those who had failed to seroconvert. Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti–IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs. [ABSTRACT FROM AUTHOR]

Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations. [ABSTRACT FROM AUTHOR]

Successful pregnancy relies on a coordinated interplay between endocrine, immune, and metabolic processes to sustain fetal growth and development. The orchestration of these processes involves multiple signaling pathways driving cell proliferation, differentiation, angiogenesis, and immune regulation necessary for a healthy pregnancy. Among the molecules supporting placental development and maternal tolerance, the families of pregnancy-specific glycoproteins and galectins are of great interest in reproductive biology. We previously found that PSG1 can bind to galectin-1 (GAL-1). Herein, we characterized the interaction between PSG1 and other members of the galectin family expressed during pregnancy, including galectin-3, -7, -9, and -13 (GAL-3, GAL-7, GAL-9, and GAL13). We observed that PSG1 binds to GAL-1, -3, and -9, with the highest apparent affinity seen for GAL-9, and that the interaction of PSG1 with GAL-9 is carbohydrate-dependent. We further investigated the ability of PSG1 to regulate GAL9 responses in human monocytes, a murine macrophage cell line, and T-cells, and determined whether PSG1 binds to both carbohydrate recognition domains of GAL-9. Additionally, we compared the apparent affinity of GAL-9 binding to PSG1 with other known GAL-9 ligands in these cells, Tim-3 and CD44. Lastly, we explored functional conservation between murine and human PSGs by determining that Psg23, a highly expressed member of the murine Psg family, can bind some murine galectins despite differences in amino acid composition and domain structure. [ABSTRACT FROM AUTHOR]

CARD11 encodes a large scaffold protein responsible for integrating antigen-receptor engagement with downstream signaling to NF-kB and other outputs in lymphocytes. Over the past 10 years, several human-inborn errors of immunity have been linked to pathogenic CARD11 mutations. Most recently, severe atopic patients were discovered that carried heterozygous dominant-negative CARD11 mutations. Here, we review the mechanistic connections between attenuated CARD11 signaling, elevated IgE, and atopy, comparing and contrasting key insights from both human patients and murine models. Continued investigation of abnormal CARD11 signaling in both contexts should inform novel therapeutic strategies to combat allergic pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract As part of an effort to identify druggable diacylglycerol kinase alpha (DGKα) inhibitors, we used an in-silico approach based on chemical homology with the two commercially available DGKα inhibitors R59022 and R59949. Ritanserin and compound AMB639752 emerged from the screening of 127 compounds, showing an inhibitory activity superior to the two commercial inhibitors, being furthermore specific for the alpha isoform of diacylglycerol kinase. Interestingly, AMB639752 was also devoid of serotoninergic activity. The ability of both ritanserin and AMB639752, by inhibiting DGKα in intact cells, to restore restimulation induced cell death (RICD) in SAP deficient lymphocytes was also tested. Both compounds restored RICD at concentrations lower than the two previously available inhibitors, indicating their potential use for the treatment of X-linked lymphoproliferative disease 1 (XLP-1), a rare genetic disorder in which DGKα activity is deregulated. Graphical abstract Image 1 Highlights • A potent DGKα inhibitor (AMB639752) has been identified via virtual screening. • Available DGKα inhibitors (ritanserin) are serotonin receptors antagonist. • AMB639752, instead, does not perturb serotonin signaling. • AMB639752 restores restimulation induced cell death in SAP deficient lymphocytes. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and has been strongly implicated in the etiology of multiple epithelial and lymphoid cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma and post-transplant lymphoproliferative disorder. There is currently no licensed prophylactic vaccine for EBV. Most efforts to develop prophylactic vaccines have focused on EBV gp350, which binds to CD21/CD35 to gain entry into B cells, and is a major target of serum neutralizing antibody in EBV seropositive humans. However, a recombinant monomeric gp350 protein failed to prevent EBV infection in a phase II clinical trial. Thus, alternative or additional target antigens may be necessary for a successful prophylactic vaccine. EBV gH/gL and gB proteins coordinately mediate EBV fusion and entry into B cells and epithelial cells, strongly suggesting that vaccination with these proteins might elicit antibodies that will prevent EBV infection. We produced recombinant trimeric and monomeric EBV gH/gL heterodimeric proteins and a trimeric EBV gB protein, in addition to tetrameric and monomeric gp350 1–470 proteins, in Chinese hamster ovary cells. We demonstrated that vaccination of rabbits with trimeric and monomeric gH/gL, trimeric gB, and tetrameric gp350 1–470 induced serum EBV-neutralizing titers, using cultured human B cells, that were >100-fold, 20-fold, 18-fold, and 4-fold higher, respectively, than monomeric gp350 1–470 . These data strongly suggest a role for testing EBV gH/gL and EBV gB in a future prophylactic vaccine to prevent EBV infection of B cells, as well as epithelial cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Antigen multimerization can markedly enhance antigenicity. [•] Novel methods for efficient production of multimeric antigens have vaccine relevance. [•] A multimeric protein vaccine is produced using a peptide spacer and leucine zipper. [•] Multimeric EBV protein, gp350, is markedly more immunogenic than monomeric gp350. [•] This method for multimerization of proteins has potential broad applications. [ABSTRACT FROM AUTHOR]

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is a proven oncogene that is essential for transformation of human B cells by the virus. LMP1 induces constitutive activa- tion of several signal transduction pathways involving nuclear factor KB, phosphatidylinositol 3-kinase/Akt, and the mitogen- activated protein kinases (MAP K) p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (Erk). Sequenc- ing of LMP1 isolated from a panel of EBV[sup+] B cell lymphomas identified three different variants of LMP1, each distinct from the B95.8 prototype isoform. All tumor variants of LMP1 as well as the B95.8 LMP1 isoform were able to induce rapid p38 phos- phorylation as well as Akt and JNK activation. Additionally all variants showed similar ability to activate nuclear factor KB. In contrast, only tumor-derived LMP1 variants induced prolonged Erk activation and c-Fos expression. Sequence analysis revealed only two amino acids, 212 and 366, shared by the tumor variants but distinct from B95.8. Point mutation of either amino acids 212 (glycine to serine) or 366 (serine to threonine) from the B95.8 isoform to the tumor variant version of LMP1 was suffi- cient for gain of function characterized by sustained activation of Erk and subsequent c-Fos induction and binding to the APi site. Our results indicate that the enhanced ability of tumor- derived LMP1 to induce and stabilize the c-Fos oncogene can be localized to two amino acids in the C terminus of LMP1. [ABSTRACT FROM AUTHOR]