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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.
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.
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.
How microglia sense amyloid plaques in Alzheimer’s disease has remained mysterious. Lemke and colleagues report that TAM receptor kinases are absolutely required for normal microglial recognition of, response to and phagocytosis of Aβ plaques. Surprisingly, TAM-mediated microglial phagocytosis of Aβ material does not constrain, but rather promotes, the formation of dense-core plaques.
FOXP3 deficiency leads to dramatic loss of immune homeostasis. This multicenter collaborative group finds that loss of FOXP3 function only disrupts a few core genes, but this unmasks a degree of systemic inflammation, and it is this environment that then strongly perturbs Treg cells.
Viral pathogens frequently target host cell antigen-processing pathways, including MHC-I–TAP peptide transporters, to evade host immunity. Blander and colleagues describe how MHC-I molecules can still cross-present antigen by re-routing ERGIC-resident MHC molecules to phagosomal vesicles, where phagolysosomal proteases act to shape the peptide repertoire for MHC-I presentation.
The E3 ubiquitin ligase MDM2 inhibits the tumor suppressor p53 and is an important therapeutic target. Zou and colleagues demonstrate that MDM2 also has a T cell-intrinsic role that supports antitumor responses.
Ting and colleagues use multi-omics to examine the alterations undergone by CD4+ T cells following HIV-1 infection. They describe mechanistic changes that lead to elevated oxidative phosphorylation, which, if inhibited, leads to suppression of HIV-1 infection.
Sharma and colleagues identify the kinase DAPK3 as a positive regulator of the STING–interferon-β activation pathway. DAPK3 acts to modify E3 ubiquitin ligases that regulate STING K63-linked poly-ubiquitination.
Growing evidence suggests that immune dysregulation is involved in the pathogenesis of myelodysplastic syndromes (MDSs). Glimcher and colleagues report haplosufficiency of the serine–threonine kinase RIOK2 leads to increased IL-22 production that, in turn, suppresses erythropoiesis. Blocking IL-22 rescues this defect in mice, suggesting that IL-22 blockade might be of therapeutic value in treating MDSs.
Kollias and colleagues examine the development of fibroblastic reticular cells (FRCs) during lymphoid organogenesis in gut Peyer’s patches (PPs). They show that PP FRCs develop from two separate mesenchymal cell lineages, which converge and form mosaic microenvironments that support immune cell activation and maintain intestinal homeostasis.
Mucida and colleagues examine how the gut epithelial microenvironment alters CD4+ T cells during their conversion into intraepithelial lymphocytes. They reveal a stepwise process involving chromatin accessibility and transcription changes triggered by ThPOK downregulation.
The contribution of T cells to the SARS-CoV-2 response remains an important and unresolved question. Moss and colleagues examine T cell and antibody kinetics in a large cohort of patients with COVID-19 and find robust and durable T cell responses.
Gounari and colleagues examine how the Wnt–β-catenin signaling axis in regulatory T cells promotes inflammatory bowel disease and colonic dysplasia. Activated β-catenin induces epigenetic changes that alter expression of genes co-regulated by Foxp3 and TCF-1.
T cells are highly dynamic and their spatial and cellular interactions can influence their differentiation program. Groom and colleagues use three-dimensional spatial imaging to show that effector and stem-like memory cell fates are imposed within distinct lymph node regions.
The transcription factor IRF8 is required for both DC and monocyte differentiation from common myeloid progenitors. Tamura and colleagues identify an enhancer (+56 kb) in the Irf8 locus that regulates early myeloid lineage choice.
Lymphocyte homing to the gut and Peyer’s patches requires expression of integrin α4β7. Ballet and colleagues report that B cell expression of CD22 is required to specifically retain surface expression of β7 integrin molecules, thereby promoting B cell retention in the gut and optimal gut mucosal antibody responses.
Rapid urbanization can be associated with adverse health implications. de Mast and colleagues compare urban and rural Tanzanian populations using multi-omics and observe that urbanization is associated with an elevated but reversible inflammatory state.