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People & Ideas

Sara Suliman is an assistant professor in the Department of Experimental Medicine at UCSF. Her lab uses multiple approaches to identify candidate tuberculosis (TB) risk pathways and to determine their role in TB progression.

Insights

Postmortem microstructural studies together with in vivo magnetic resonance imaging show that human arachnoid granulations are porous channels that serve as transient filtration conduits for cerebrospinal fluid to flow directly into dural interstitial tissue, but not into venous sinuses.

In the mouse, γδIL17 cells are poised to make IL-17, and these cells have been involved in various infection and cancer models. Edwards et al. now report how different γδIL17 subsets are controlled during homeostasis and cancer.

In this issue of JEM, Tanaka et al. advance our understanding of how genetic mutants that decrease T cell recognition of antigen, a critical event for immune activation to invading microbes and virus, paradoxically results in autoimmunity.

Viewpoint

Daniela Salvemini and Timothy Doyle discuss the opportunity to target pro-inflammatory neuro-immune cell interactions in the treatment of neuropathic pain.

Perspectives

The animal model for experimental encephalomyelitis, first published 90 yr ago, continues to illuminate mechanisms of disease. The model, initially developed to understand how smallpox triggers neuroinflammation on rare occasions, now moves full circle to its origins.

Brief Definitive Reports

Arachnoid granulations are poorly investigated. We show that they harbor immune cells and communicate with perisinus spaces, suggesting that granulations subserve neuroimmune roles and function as transarachnoidal passageways. These data raise new theories regarding glymphatic–lymphatic coupling and mechanisms of diseases.

Nielsen and Zhang et al. show that well-established, Notch4-induced brain arteriovenous malformations are normalized, following deletion of the Notch signaling mediator, Rbpj. Upon complete regression, virtually no AVM relapses in adults, even when the causal factor is reintroduced.

Koike et al. employ a time-stamping method for plasma cells and measure the decay of the homeostatic plasma cells with distinct isotypes, or antigen-specific plasma cells that are generated in germinal center–independent or –dependent pathway.

The study identifies a unique role for early T-bet expression in promoting the proliferation of antigen-specific CD8+ T cells following vaccination. Early T-bet expression is necessary for optimal LFA1 expression for appropriate cellular interactions and enables optimal expansion and differentiation of effector and memory CD8+ T cells.

In Special Collection: JEM Immunology Collection 2023

We report a new mechanism of immune evasion by SARS-CoV-2 based on direct disabling CTLs to form immune synapses through Spike protein binding to ACE2. This mechanism could contribute to the failure of the immune system to control SARS-CoV-2 infection.

Articles

Coffelt, Edwards, and colleagues provide deep phenotypic analysis of mouse γδ T cells. They focus functional studies on IL-17A–producing γδ T cell subsets, showing that the co-inhibitory molecules, PD-1 and TIM-3, regulate cell expansion in tumor-bearing mice, which counteracts anti–PD-1 or anti–TIM-3 immunotherapy.

How an anomaly in a TCR signaling molecule leads to spontaneous autoimmunity over immunodeficiency is unclear. Qualitative/quantitative reduction of ZAP-70 to a critical range produces autoimmune T cells and impairs Treg function, together eliciting autoimmune arthritis and colitis in mice.

Inherited CARMIL2 deficiency underlies infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation. CARMIL2 deficiency impairs CD28 signaling only partially in T cells. The comparison of CARMIL2 and CD28 deficiency in humans suggests that CARMIL2 governs immunological pathways beyond CD28.

Zhou et al. establish murine models of anti-CTLA-4–mediated intestinal irAEs. These reveal common immune signatures and the importance of fecal microbiome dysbiosis as irAE-driving mechanisms, which enable preclinical therapeutic interventions. Key immune features are validated in a cohort of melanoma patients with ICB-associated intestinal irAEs.

Using systemic EC–pericyte crosstalk analysis, this study identifies the NO–sGC as a key signaling that mediates EC–pericyte communication in the lung vasculature and demonstrates that pharmacological activation of the NO–sGC signaling promotes vascular integrity and mitigates inflammation-induced lung injury.

Using epigenomics, transcriptomics, and functional studies, we define mechanisms through which interleukin-33 (IL-33) promotes microglial synapse engulfment during brain development and restricts seizure susceptibility, in part via the induction of pattern recognition receptors including the scavenger receptor MARCO.

Inoue et al. show that the antibody feedback plays a role in generating Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.

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