Issues

In this opinion article, Silva-Santos et al. discuss the potential of Vδ1⁺ γδ T cells for cancer immunotherapy, focusing on DOT cells. These in vitro–expanded γδ T cells display strong and broad cytotoxicity against hematological and solid tumors, which can be further enhanced upon transduction with CARs.

CRISPR screens are transforming how immune regulation is studied. In this Perspective, Shi and Chi survey emerging bulk, single-cell, spatial, and combinatorial CRISPR screening platforms. They highlight how these approaches reveal causal immune mechanisms across complex microenvironments and identify therapeutic targets for disease.

Zhang et al. report a fatal case of avian influenza H5N1 infection caused by autoantibodies neutralizing type I IFNs. These rogue autoantibodies are common, especially in elderly people. They are found to underlie a growing range of severe infections of emerging and circulating viruses, including seasonal influenza viruses and SARS-CoV-2.

Specialized fibroblasts in secondary lymphoid tissues are essential for generating effective lymphocyte responses. Here, we characterize and spatially map the fibroblast landscape within human large and small intestinal gut-associated lymphoid tissues, including Peyer’s patches and isolated lymphoid follicles, during homeostasis and Crohn’s disease.

Single-cell and spatial transcriptomics of human TB lung tissues from individuals in South Africa revealed that MMP1⁺CXCL5⁺ fibroblasts and SPP1⁺ macrophages are linked to TB disease and TB lung granuloma, uncovering targetable cellular cross talk underlying TB immunopathology and potential avenues for host-directed therapies.

Farré Díaz et al. describe a broadly applicable system for sequential targeted mutagenesis using two recombinases sequentially activated from a single locus. As a proof-of-concept experiment, the time-controlled re-expression of FOXO1 rescued the defects associated with FOXO1-deficient germinal center B cells, including class switch recombination, providing new insights into FOXO1 biology via a dual-recombinase tool.

Immune responses to pathogens lead to the generation of plasma cells containing the infection by secreting high-affinity antibodies. Here, we describe an in vivo CRISPR/Cas9 screening system for identifying novel regulators of B cell activation and plasma cell development in the context of the splenic microenvironment of immunized mice.

In response to intratumoral hypoxia, breast cancer cells co-opt an antiviral mechanism to promote cancer stem cell specification and immune evasion, which are essential properties that enable metastasis.

Antibiotic treatment in early life can deplete riboflavin-synthesizing commensals and impair mucosal-associated invariant T (MAIT) cell development, rendering adult animals more susceptible to bacterial pneumonia. Transfer of MAIT cells or administration of a riboflavin-synthesizing probiotic is sufficient to restore respiratory immunity.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses. In 149 international FVH patients, auto-Abs neutralizing type I interferons are found in 37.5% of HSV-triggered cases and are absent in hepatitis A and B virus–triggered cases, increasing the risk of HSV-FVH by >1,800-fold.

Bittar et al. describe expanded clones of authentic CD4⁺ T cell carrying intact latent HIV-1 proviruses derived from people living with HIV. Their transcriptome mirrors their primary cells of origin. Notably, only a fraction of clonal cells express HIV. Latency-reactivating agents induce modest and variable activation, highlighting challenges in pharmacologic approaches to reservoir elimination.

Oral antigen exposure combined with CD28 costimulation blockade generates functionally stable antigen-specific CD101⁺ pTreg cells even in previously antigen-sensitized hosts. This way of establishing antigen-specific oral tolerance enables halting progression of allergy and autoimmune disease and treating them.

Březina et al. demonstrate that Claudin 1 enables thymic type 1 dendritic cells to localize within proximity to medullary thymic epithelial cells. This spatial arrangement supports maturation and tolerogenic function of type 1 dendritic cells, thus preventing disruptions in T-cell tolerance.

Siniscalco et al. reveal that DOCK8 and STAT3 cooperate in CD4⁺ T cells to restrain Tfh13 differentiation and prevent food-specific IgE. The DOCK8-STAT3 axis functions cell-intrinsically within T cells to limit GATA3 expression and Tfh13 cell differentiation, while additional Treg impairment in DOCK8 deficiency uniquely enables Tfh13 induction in the gut.

Horton et al. report that force generated by blood flow within the developing embryo dictates a bioenergetic switch necessary for hematopoietic stem cell emergence. Shear stress triggers protein translation and transcriptional upregulation of mitochondrial genes via mTORC1 to endow stem cells with blood reconstitution capacity.

Xu et al. demonstrate that FIP200, a sensor involved in autophagy regulation, governs the differentiation of plasma B cells. B cells without FIP200 are dysfunctional in mitophagy and metabolism. Adding heme can rescue this phenotype and allow plasma cell differentiation.

Our study demonstrates CD205 is upregulated in prePCs. H3K27 demethylase Kdm6b, not Kdm6a, allows prePCs to become bona fide PCs by removing H3K27me3 marks at the Irf4 locus. Interestingly, prePCs favor glutamine metabolism, which provides α-ketoglutarate as a substrate for the demethylation reaction of Kdm6b.