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Clarke and colleagues show that germinal center B cells have highly dynamic mitochondria, which are regulated by the transcription factor TFAM. TFAM activity is required to promote spatial entry into the germinal center reaction by modulating cellular motility.
Becher et al. perform a head-to-head comparison of multiple severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) vaccine prime-boost combinations and analyze the ensuing humoral and cellular responses in a large randomized cohort.
In non-small cell lung cancer, the presence of monocyte-derived macrophages inversely correlates with the presence of NK cells. Merad and colleagues propose that when monocytes phagocytose tumor debris they express TREM2, become pro-tumorigenic, and suppress NK cell recruitment and activation in tumors.
CAR T cell success requires targeting tumors, but these cells can get trapped in other tissues, such as in the lungs, where they can cause pathology. Here, the authors use a loss-of-function CRISPR screen to identify regulators of CAR T cell tumor trafficking and engineer CAR T cells accordingly to overcome this limitation.
Khader and colleagues show Mycobacterium tuberculosis (Mtb)-specific B cells are needed to recruit TFH cells into follicular-like structures within lung granulomas to control the Mtb bacilli; however, specific antibodies and many conventional properties of B cells are dispensable.
APLAID is a rare autoinflammatory disorder driven by mutations in PLCG2. Here the authors provide a new mouse model using the human APLAID p.Ser707Tyr mutation. The mouse recapitulates clinical features of APLAID that can be prevented by anti-G-CSF. Individuals with APLAID were also shown to have high circulating levels of G-CSF suggesting this might be a suitable target for the clinic.
NK cells require an immunological synapse to kill cancer cells and these synapses have been shown to have membranous protrusions. Here the authors use cutting-edge imaging and other techniques to show that tumor serine metabolism results in a reduction in NK cell sphingomyelin content and a lack of these membranous protrusions, which could contribute to a failure to kill cancer cells.
Singer and colleagues show that the developmental fate of autoreactive CD4+ thymocytes is determined by the timing and duration of agonist signaling. Early agonist signaling induces clonal deletion, whereas late agonist signaling induces differentiation into Foxp3+ Treg cells or IL-2+ Teff cells depending on whether TGF-β disrupts TCR signaling.
Kamiya and colleagues examine the effects of chronic social-defeat stress on the intestinal microbiome and show a pathological role played by dectin-1 and interleukin-17 expressed by gut γδ T cells on this behavioral vulnerability.
γδ T cells contribute to cancer immunity by killing tumor cells, but their function in the context of immune checkpoint inhibition is less clear. Here the authors show that a Vδ2− subset of γδ T cells in human kidney tumors phenotypically resembles exhausted T cells yet retains this cytolytic function and can be used to predict response to immune checkpoint inhibition.
Here the authors show that unlike IL12, IFNγ can induce a T helper 1-like state in regulatory T (Treg) cells during viral infection in mice that suppresses effector T cell responses and memory formation.
Marichal and colleagues use a model of niche depletion and refilling to show that engrafted Ly6C+ classical monocytes proliferate locally in a Csf1 receptor-dependent manner before differentiating into lung interstitial macrophages.
Cheng et al. demonstrate that an extra copy of the X-linked epigenetic regulator UTX in females increases natural killer (NK) cell effector function. As NK cells are critical for antiviral immunity, this may explain decreased severity of viral infections in females compared to males.
Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.
Zhang and colleagues perform functional, biochemical and structural analysis of a set of antibodies isolated from COVID-19 convalescents infected with wild-type SARS-CoV-2 during the first wave of the pandemic and show they have broad neutralizing activity against all SARS-CoV-2 variants tested, including omicron.
Here, the authors show that CD8+ T cells egress from tumors via lymphatic vessels in a CXCL12/CXCR4-dependent manner. High-affinity antigen encounter inhibits CXCR4 and increases retention, while no encounter or weak affinity directs T cell exit to limit local tumor control.
Unlike metabolic reprogramming that is characteristic of macrophage inflammatory polarization responses to lipopolysaccharide and TLR4 stimulation, the metabolism underlying inflammatory responses to CD40 signaling is not well characterized. Here the authors show CD40 signaling drives fatty acid oxidation and glutamine metabolism resulting in regulation of the NAD+/NADH ratio, which in turn promotes antitumor and pro-inflammatory macrophage functions.
Type 1 diabetes is associated with homozygous expression of specific major histocompatibility complex class II beta chain polymorphisms. Here the authors show that the disease-protective effect of major histocompatibility complex class II heterozygosity is conferred by non-cognate thymocyte negative selection.
Here, the authors show that acute influenza infection induces trained immunity in self-sustaining resident alveolar macrophages, which independently exert long-term antimetastatic immune surveillance in the lung via enhanced tumor killing.
Here the authors show that dihydroorotate dehydrogenase in the de novo pyrimidine synthesis pathway functions as a cell fate checkpoint that can be targeted to specifically diminish the number and function of effector T cells without affecting the memory T cell pool and response to infection.