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The zinc-finger transcription factor IKAROS is essential for B cell development. Taniuchi, Morio and colleagues identify a human kindred presenting with B cell immunodeficiency that was caused by a heterozygous missense mutation in IKZF3 encoding the related AIOLOS protein. AIOLOSG159R is a mutant protein that interferes with both wild-type AIOLOS and IKAROS by forming heterodimers that bind to aberrant DNA-binding sites and prevent normal expression of IKAROS-dependent genes.
Effective control of tumors requires the presence of inflammatory helper and cytotoxic T cells. Song and colleagues demonstrate that the protein RGS1 cell-intrinsically regulates effector T cell homing to tumors and thereby impairs tumor control.
Brown and colleagues generated an atlas of miRNA expression profiles from primary mouse immune cell populations and connected these signatures with ATAC–seq, ChIP–seq and nascent RNA profiles to establish a map of miRNA promoter and enhancer usage in immune cells.
Group 2 innate lymphoid cells (ILC2s) are generally considered to have pro-tumor functions. However, Belz and colleagues demonstrate that ILC2s have anti-melanoma effects due to their high production of the inflammatory cytokine granulocyte-macrophage colony-stimulating factor in the tumor microenvironment.
Korn and colleagues demonstrate that the site of T cell priming (gut versus skin draining lymph nodes) dictates their effector phenotypes and homing to distal sites of immunopathology.
Invariant natural killer T (iNKT) cells populate barrier surfaces during an early-life window. Blumberg and colleagues demonstrate that such barrier surface iNKT cells develop via an extrathymic pathway dependent on a specialized population of embryo-derived macrophages.
Heeger and colleagues report that activated B cells dynamically regulate the expression of complement regulatory proteins via the transcription factor BCL6. C3 convertase activity and C3aR1–C5aR1 signaling were both necessary for optimal B cell activation and germinal center formation.
Raychaudhuri and colleagues use high-dimensional single-cell analysis of T cells from a human tuberculosis progression cohort. They identify a TH17–like cluster reactive to Mycobacterium tuberculosis peptides that is reduced in people who previously progressed to active disease.
Tang and colleagues show that a half-life-extended IL-10–Fc fusion protein acts directly on terminally exhausted PD1+TIM-3+CD8+ T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier–dependent manner. Treatment of tumor-bearing mice with IL-10–Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures.
Xu and colleagues use single-cell transcriptomic analyses to uncover distinct expression dynamics of metabolic programs in germinal center B cells. Coupled analysis of transcriptional states and Igh variable sequences revealed that OXPHOS metabolism is enhanced in GC B cells undergoing positive selection. Their findings suggest BCR signaling tunes GC B cell metabolism to accelerate the cell cycle of positively selected GC B cells.
Chromatin undergoes extensive reprogramming during immune cell differentiation. Here Kuo and colleagues uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.
Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.
Multiple myeloma disease progression and therapy response are influenced by the bone marrow niche in which the tumor cells reside. To characterize this supportive niche, Cupedo and colleagues use single-cell transcriptomic analysis of bone marrow stromal cell populations from individuals with multiple myeloma. They identify a myeloma-specific inflammatory mesenchymal stromal cell (iMSC) population that spatially colocalizes with tumor cells. Anti-myeloma induction therapy does not influence iMSC presence, suggesting a role for bone marrow inflammation in myeloma persistence or relapse.
RIG-I is a cytosolic nucleic acid sensor triggering type I IFN production. Takaoka and colleagues find that RIG-I recognizes SARS-CoV-2 RNA in a noncanonical manner and fails to activate type I IFN, but it directly restricts viral replication.
The innate sensors of SARS-CoV-2 are still being determined. Kanneganti and colleagues find that SARS-CoV-2 envelope protein is sensed by TLR2 and this drives pathogenic inflammatory cytokine production.
Dick and colleagues identify human LT-HSC subsets with distinct quiescent states. They link these differences to INKA1-mediated downregulation of the transmembrane protein CD112 and its interaction with the protein deacetylase SIRT1. INKA1 is inversely correlated with the histone H4K16Ac mark, which then distinguishes ‘latent’ CD112lo LT-HSCs from CD112hi LT-HSCs that are more readily activated in response to hematopoietic stress.
Immune cells exert important effects on white adipose tissue (WAT) in metabolic diseases. O’Sullivan and colleagues generate a comprehensive single-cell atlas of WAT cells in both health and disease to identify new cellular networks and differentiation trajectories.
Tumor-associated macrophages (TAMs) play multifaceted roles in establishing an immunosuppressive tumor microenvironment. Sica and colleagues find that macrophage-intrinsic complement signaling initiates a pathway leading to the induction of highly tumorigenic TAMs.
Fibroblastic reticular cells (FRCs) provide structural support and soluble factors necessary for proper lymph node organization and function. Turley and colleagues use scRNA-seq to identify a unique Gremlin1-expressing FRC subset that is found in T cell zones. Grem1+ FRCs support the survival of resident cDCs and are necessary to promote T cell immunity.
Malaria immunity can be acquired through natural infection, but the correlates of protection are still being determined. Yazdanbakhsh and colleagues combine experimental infection of volunteers with Plasmodium falciparum with systems analysis to throw light on the nature of protective immune responses.