Gut dysbiosis has long been associated with the development of Crohn's disease and other gastrointestinal disorders. Otake-Kasamoto et al. report that dysbiotic microbiota–derived bioactive lipids, lysophosphatidylserines, can promote pathological Th1 cell responses through inducing metabolic reprogramming and epigenetic changes.
The cytokine LIGHT (TNFSF14) has emerged as an important modulator of innate and adaptive immune responses. Accumulating basic and clinical evidence points to the dysregulation of the LIGHT network as a disease-driving mechanism and supports the application of target-modifying therapeutics for disease intervention.
This review traces the separate discoveries of dendritic cells, cross-priming, and help for cytotoxic T cell responses. The authors document the gradual convergence of these discoveries into the current models of cell-mediated immunity, spotlighting unanswered questions and future directions.
As the first immune cells to colonize tissues and long-lived resident cells, macrophages play important roles in tissue functions during early development, homeostasis, and disease. Here, Chakarov et al. discuss macrophage origin and functions in adipose tissue and how these features are modulated in obesity.
Brief Definitive Reports
Campbell et al. describe seven IRF7-deficient patients with severe respiratory viral infection. Combining genetic, immunological, and clinical investigation, they highlight the surprisingly narrow disease susceptibility of IRF7 deficiency and reveal potential compensatory immunological mechanisms, including IFN-β and adaptive immunity.
Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors
We report a patient with a broad and lethal EBV infection mainly characterized by disseminated EBV-associated smooth muscle tumors. The patient was a carrier of a homozygous loss-of-function mutation in TNFSF9 that impaired expansion of EBV-specific T cells.
CXCR4+ Treg cells control serum IgM levels and natural IgM autoantibody production by B-1 cells in the bone marrow
Inducible CXCR4 ablation in Treg cells results in dysregulation of B-1 B cells in the bone marrow due to local Treg cell depletion, leading to an increase in IgM autoantibody production and total IgM levels.
This study shows that Crohn’s disease–associated microbiota generate lysophosphatidylserines that promote Th1 responses by fueling glycolysis. Lysophosphatidylserine-induced aggravation of colitis is prevented by P2y10 deficiency in CD4+ T cells, demonstrating that dysbiotic microbiota-derived LysoPS exacerbates colitis by modulating Th1 cell metabolism.
Boieri et al. demonstrate that CD4+ T helper cells directly block breast cancer development by forcing the cancer cells to terminally differentiate.
MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity
Katsouda et al. describe the impact of the sulfide species–generating enzyme MPST in energy homeostasis and metabolic health. Mpst−/− mice placed on high-fat diet exhibit attenuated mitochondrial protein import, mitochondrial dysfunction, enhanced lipid accumulation, adipocyte enlargement, and excessive weight gain. Therapeutic sulfide administration ameliorates obesity-related molecular and phenotypic changes.
High-fat/high-sugar diet–expanded microbiota promote insulin resistance inducing Mmp12-positive adipose macrophages via TLR2/MYD88 and ATF3. Mmp12-positive adipose macrophages exhibit a transcriptomic signature associated with insulin resistance in humans.
The authors describe a noncanonical role for multiple chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I in autoimmune diseases.
Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming
Wang et al. systematically characterize the dynamic nature of β cell functional and transcriptomic adaptation along the progression of diet-induced obesity and T2D. They also identify CTCF as a key mediator of dietary intervention–induced preservation β cell function via transcriptional reprogramming.
Potent human broadly SARS-CoV-2–neutralizing IgA and IgG antibodies effective against Omicron BA.1 and BA.2
This study identifies broadly SARS-CoV-2–neutralizing IgA and IgG antibodies from Wuhan COVID-19 convalescents active against the variants of concern Alpha, Beta, Gamma, Delta, and Omicron BA.1 and BA.2.
Network analysis of IL-2 identifies a context-dependent hierarchy of consumption and response. IL-2 sourced from different leukocytes drives different circuits of responding cells, independent of concentration. Targeting IL-2 localization may therefore allow fine-tuning of therapeutic responses.
Vitamin B12 coordinates ileal epithelial cell and microbiota functions to resist Salmonella infection in mice
Vitamin B12 shapes gut microbiome and supports mitochondrial metabolism of ileal epithelial cells to synergistically regulate epithelial oxygenation, controlling aerobic Salmonella infection. This mechanistic interplay highlights the significance of this crucial micronutrient in maintaining intestinal homeostasis against pathogen infections.