People & Ideas
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 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.
Daniela Salvemini and Timothy Doyle discuss the opportunity to target pro-inflammatory neuro-immune cell interactions in the treatment of neuropathic pain.
Experimental encephalomyelitis at age 90, still relevant and elucidating how viruses trigger disease
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 lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma
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.
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.
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.
Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency
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.
Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury
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.
Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice
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.
Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees
Inoue et al. show that the antibody feedback plays a role in generating Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees.