Issues

In this issue, the Casanova group identifies bi-allelic loss-of-expression, loss-of-function mutations of the calcium- and integrin-binding protein 1 (CIB1) gene as a new cause of epidermodysplasia verruciformis (EV) and demonstrate that the CIB1 interacts with the EVER1 and EVER2 proteins to form a complex involved in keratinocyte-intrinsic immune response to human β-papillomaviruses (β-HPVs).

In this issue of JEM, Marijt et al. report their discovery of 16 novel human TAP-independent TEIPP peptides, whereas only one had been previously identified. This opens the door to new therapeutic options for patients with TAP-deficient tumors.

Microglia are central players in homeostasis and disease. Kang et al. reveal a novel ApoE-driven microglial pathway shared between aging, amyloidosis, and tauopathy that is exacerbated in females, suggesting a convergent mechanism for altering microglial reactivity during Alzheimer’s disease.

Chakrabarty et al. show that human TLR5 ectodomain reduces amyloid β (Aβ) plaques by direct interaction with Aβ, demonstrating the feasibility of such immune decoy receptor strategies as potential biotherapies in Alzheimer’s disease.

Transcriptional control of dendritic cell (DC) functions is poorly understood. Lau, Tiniakou, et al. report that transcription factor ETV6 optimizes gene expression in DCs and facilitates their ability to cross-prime T cells and initiate tumor-specific immune responses.

Lee et al. generate knock-in mice with critical residues mutated in caspase-11 and GSDMD. This is the first compelling genetic evidence to demonstrate the critical roles of caspase-11 catalytic and auto-proteolytic activities, as well as GSDMD cleavage in a physiological response to LPS.

de Jong et al. show that loss-of-function mutations in CIB1 are responsible for epidermodysplasia verruciformis, a cutaneous disease caused by human β-papillomavirus (β-HPV) infections, and that CIB1 forms a complex with EVER proteins, acting as a restriction factor against HPV.

In the setting of a clinical trial evaluating the anti–HIV-1 antibody 3BNC117, Cohen et al. demonstrate that rebound viruses that emerge following interruption of antiretroviral therapy are distinct from circulating latent viruses. Rebound viruses often appear to be recombinants between isolated latent viruses.

A hybrid forward-reversed immunological screen is performed to identify 16 novel HLA-A2 presented cancer antigens. These peptides are selectively presented by immune-escaped cancer cells with defects in the peptide transporter TAP. In contrast to mutated neoantigens, these “self” neoantigens are universally presented across different cancer types.

Using genetic, pharmacological and animal model approaches, we elucidate a novel human mutation in a G protein coupled receptor that impairs receptor oligomerization and trafficking leading to fatal, non-immune hydrops fetalis associated with arrested lymphatic development.

Martini-Stoica et al. demonstrate that the TFEB-mediated lysosomal pathway in astrocytes is increased in tauopathy and plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in a mouse model of tau spreading.

“Adaptive” NK cells expressing the activating receptor NKG2C expand and persist in HCMV-seropositive individuals. Cichocki et al. demonstrate enhanced oxidative and glycolytic metabolism for adaptive NK cells and implicate ARID5B as an important regulator of mitochondrial metabolism, IFN-γ production, and survival.

This study provides strong evidence that intestinal commensal LPS desensitizes lung epithelial cells and therefore diminishes allergic responses to inhaled allergens. A host lipase, acyloxyacyl hydrolase (AOAH), prevents the desensitization by inactivating commensal LPS.

Deason et al. discover a novel signaling adapter in the IL-1R pathway in CD4⁺ T cells that controls the induction of the PI3K–mTOR pathway, downstream of IL-1β, to induce pathogenic Th17 cells involved in the development of autoimmunity.

Singh et al. show that expression of B cell adaptor for PI3-kinase (BCAP) is induced upon T cell activation and that this helps control effector and memory CD8⁺ T cell differentiation.

B cell–intrinsic activated CARD11 (aCARD11) expression promotes rapid formation and premature collapse of the germinal center while enhancing terminal differentiation due to heightened NF-κB and mTORC1 signaling.

Metabolic programs are crucial for T reg cell stability and function. Yu et al. report that TRAF3IP3 acts as a pivotal regulator in controlling metabolic fitness to maintain T reg cell stability and function at the lysosome.