Issues

Sarah Teichmann is a professor at the University of Cambridge, where she leads a group that uses genomics, AI, and bioinformatics to further understand various aspects of immunity. We spoke to Sarah about expanding beyond academia and dealing with uncertainty in the workplace.

In this issue of JEM, Leddy et al. present PathMHC, a computationally guided mass spectrometry approach that boosts the detection of pathogen immunopeptides presented on infected cells.

Yang and colleagues provide an exhaustive study of a novel mouse model of NGLY1 deficiency, a devastating neurological disease, and implicate the cGAS-STING pathway in mediating key disease features which can be rescued using an orally administered STING antagonist.

This year at JEM, we are highlighting women in science by sharing their stories and amplifying their voices. In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher.

The current review assesses all the available evidence regarding how two crucial elements are intertwined in AD pathophysiology: tau and apoE. We summarize relevant findings in human, cell, and mouse models supporting a synergistic role between these two key players.

Inactivation of calreticulin enhances antitumor immunity by reshaping the MHC-I peptide repertoire and activating tumor-specific T cells. This study identifies a novel strategy of targeting the peptide-loading complex to overcome immune evasion and improve cancer immunotherapy outcomes.

MS-based immunopeptidomics can facilitate vaccine antigen discovery, but self-MHC peptides greatly outnumber pathogen-derived MHC peptides, presenting a challenge for untargeted MS methods. Computationally identifying infection-specific MS peaks in immunopeptidomics data enables more sensitive and selective identification of pathogen-derived peptides using targeted MS.

The diversity of coronaviruses renders neutralization breadth key for vaccine and monoclonal antibody development. Using immunoglobulin knock-in mice, Nair et al. rediversify germline and mature versions of the human anti-SARS-CoV-2 spike antibody CR3022 to obtain broadened reactivity against human and bat coronaviruses.

In this study, McDaniel et al. examine the molecular features of the antibody response to the R21/Matrix-M malaria vaccine in malaria-naïve volunteers. R21/Matrix-M elicits antibodies cross-reactive with protective epitopes not included in the vaccine, offering insights into the basis of vaccine efficacy.

NGLY1 deficiency is an early-onset neurodegenerative disorder with no effective therapy. Here, we describe an inducible Ngly1 knockout mouse model, iNgly1^−/−, that reveals pronounced loss of Purkinje cells in the cerebellum without neuroinflammation. Sting1 knockout or STING inhibitor VS-X4 significantly rescues iNgly1^−/− disease in mice.

Roark et al. infect macaques with chimeric simian-human immunodeficiency viruses to induce broad HIV-1-neutralizing antibodies targeting the V2 apex site-of-vulnerability. From 10 infected macaques, 11 V2 apex-directed antibody lineages were identified, and 9 antibody-antigen complexes were characterized, collectively defining both structural repertoire and genetic basis for V2 apex recognition.

We report a newly designed germline-targeting Env SOSIP trimer, 3nv.2, that binds to bNAb precursors targeting the CD4bs, V3, and V2 epitopes. 3nv.2 forms a stable trimer, and immunization experiments in rhesus macaques and mice demonstrate 3nv.2 elicits the combined effects of its parent immunogens.

Gern et al. show that antagonistic circuits between neutrophils and CD4 T cells are established during early Mtb infection, and the relative kinetics of these responses determines the pathologic outcome of infection.

Pauken and Markson et al. show that when PD-1–expressing and PD-1 knockout CD8⁺ T cells are within the same tumor microenvironment, both cell types exhibit similarly enhanced functions, highlighting a role of cell-extrinsic changes in enhancing antitumor immunity.

This study identifies biallelic germline ASXL1 variants as the cause of a novel inborn error of immunity, linking ASXL1 deficiency to epigenetic dysregulation, combined immune deficiency, chronic viral infections, and malignancy, expanding the spectrum of genetic causes underlying human immunodeficiencies.

Shi et al. identify the type I BMP receptors ALK2 and ALK3 as critical mediators of T cell activation and activation-induced cell death, and the roles of ALK2/3 in these processes are interdependent and independent of their BMP ligands.

This study reveals that ciliated cells play an immunoregulatory role in allergic asthma by constitutively expressing IL-17D, which limits monocyte recruitment to inflamed lungs. These findings may provide a basis for developing therapies for related lung diseases.