ON THE COVER
Beck et al. show that immature B cell retention in the bone marrow is an active process, whereas egress is a passive one. B cells are retained in the bone marrow by CXCR4-CXCL12 interactions, which induce α4β1-mediated adhesion to VCAM-1. Decreased expression of CXCR4 in B cells approaching sinusoids loosens their grip and allows them to be passively swept out of the marrow. Image shows “rounded up” B cells (blue) in sinusoids in the process of passive exit. Image by New York artist Alta Buden. firstname.lastname@example.org.
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Brief Definitive Report
Modulation of orexin and its effects on sleep/wakefulness affect amyloid-β pathology in the brain of mouse models for Alzheimer’s disease.
Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignancy without a cure. Louis Staudt and colleagues identified gain-of-function mutations in the chemokine receptor CCR4 in ATLL patient samples. The mutations increased cell migration and conferred a growth advantage in ATLL cells. The findings implicate CCR4 mutations in the pathogenesis of ATLL and suggest that inhibition of CCR4 signaling may provide therapeutic potential.
Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell–dendritic cell interactions
Dendritic cell–derived thromboxane A2 (TXA2) limits T cell activation by inhibiting interactions between T cells and dendritic cells. Moalli et al., from the University of Bern, now show that the effect of TXA2 is selective for low-avidity T cells, perhaps as a way to boost the overall quality of immune responses.
CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation
Kennedy et al. identify a mutation in coiled-coil domain containing protein 88b (Ccdc88b) that confers protection against lethal neuroinflammation during experimental cerebral malaria. CCDC88B is expressed in immune cells and regulates T cell maturation and effector functions. In humans, the CCDC88B gene maps to a locus associated with susceptibility to several inflammatory and autoimmune disorders.
Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K
Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85α subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85α association with p110δ that stabilizes the catalytic subunit but fails to properly inhibit catalytic activity. The patients have immunodeficiency and lymphoproliferation with skewing of CD8+ T cells toward terminally differentiated and senescent effector cells that have shortened telomeres.
Zhang et al. show that DOCK8-deficient T and NK cells develop cell and nuclear shape abnormalities that do not impair chemotaxis but contribute to a form of cell death they term cytothripsis. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells resulting in impaired immune response to skin infection.
Joao Pereira and colleagues at Yale University show that B cell egress from bone marrow is a passive process, similar to that of red blood cells. Immature B cells that approached bone marrow sinusoids decreased their expression of CXCR4 and rounded up, allowing them to be passively swept away.
Using pharmacological activation and genetic ablation of β2-adrenergic receptors (β2ARs) in mice, Nakai et al. show that β2ARs expressed on lymphocytes can regulate egress of these cells from lymph nodes, while altering the responsiveness of chemokine receptors CCR7 and CXCR4. They identify that β2ARs can physically interact with these chemokine receptors. And, in mouse models of T cell–mediated inflammation, β2AR-mediated signals are shown to inhibit trafficking of antigen-primed T cells, reducing their numbers in inflamed peripheral tissues.
Godfrey, Rossjohn, and colleagues define a population of T cells in healthy humans that express T cell receptors (TCRs) comprised of δ variable gene segments fused to α joining and constant domains and paired with a variety of TCR-β chains. Functional and structural analyses reveal how components of αβ and γδ TCR gene loci combine to create T cells with unique patterns of antigen recognition.
Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy
Enhanced polycomb complex protein Bmi1 expression in adult stem cells of the skeletal muscle leads to improved muscle function in a model of Duchenne Muscular Dystrophy via metallothionein1-mediated protection from oxidative stress.
The adaptor protein Tespa1 negatively regulates mast cell activation, including cytokine production and degranulation. Mice lacking Tespa1 have exaggerated responses in mast cell–dependent inflammation models, including anaphylaxis and allergic inflammation.
Gao et al. show that E-box proteins dampen the generation and function of Foxp3+ regulatory T cells in part by inhibiting IL-2Rα expression and IL-2 responsiveness.
Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection
Gundula Min-Oo and Lewis Lanier show that memory NK cells generated during MCMV infection respond poorly to cytokines generated during heterologous viral or bacterial infection, as compared with naïve NK cells.