Reviews & Analysis

The transcription factor NFAT5 regulates T cell exhaustion, a dysfunctional state caused by chronic exposure to antigen and other signals, during cancer but not during chronic viral infection.

IRF4 is required for the differentiation of T cells, B cells and some myeloid cells. A new study finds that IRF4 is upregulated following natural killer (NK) cell activation and is required for the differentiation and expansion of virus-specific NK cells by controlling nutrient acquisition, including iron uptake.

A recent study identified a microglia–T cell communication axis that retains CD8⁺ T cells in brains with amyloid pathology. Data from this study indicate that CD8⁺ T cells restrict Alzheimer’s disease pathogenesis.

Glioblastoma is a devastating primary brain tumor consisting of multiple cell populations. We identified TFPI2 as the crucial effector of the symbiotic interaction between glioblastoma stem cells and microglia. Blockade of this symbiosis inhibited tumor growth and synergized with an immune checkpoint inhibitor in mouse models of glioblastoma.

Proal and colleagues review the evidence for long-term persistence of coronavirus SARS-CoV-2 in tissues of infected individuals and discuss how this viral reservoir may contribute to the pathogenesis of post-acute sequelae of COVID-19 (PASC).

Control of the alternative commitment of immature CD4⁺CD8⁺ T cells to the CD4⁺ or CD8⁺ lineage has long been the subject of intense scrutiny. A combination of CITE-seq and functional assays provides significant new insights into the distinct T cell antigen receptor signaling requirements for these lineage fates.

A recent study shows how intratumoral glutamine supplementation can improve the function of tumor-infiltrating dendritic cells and enhance the CD8⁺ T cell anti-tumor response.

Human mucosal-associated invariant T (MAIT) cells exhibit many functions, but whether this reflects different subsets is unknown. We defined the transcriptional and clonal landscape of MAIT cells in human blood and liver. Our study reveals limited transcriptional variation within tissues, but marked phenotypic and functional plasticity according to tissue, clone, and most notably, stimulus.

In a genome-wide protein quantitative trait locus study, we identify the genetic determinants of the levels of 91 inflammation-related proteins in blood from over 15,000 people. By combining these data with studies on the genetics of immune-mediated diseases, we reveal how individual proteins contribute to specific disease risks.

Malaria is a vector-borne disease caused by Plasmodium parasites. In an exciting new study, Ganley et al. harness the power of mRNA vaccines to summon tissue-resident memory T cells to battle the parasite as it replicates in the liver.

The functional heterogeneity of macrophages has ontological and microenvironmental bases, and differentially affects pathology. In pancreatitis, tissue-resident macrophages promote protective fibrosis that favors the maintenance of pancreatic homeostasis. In pancreatic ductal adenocarcinoma, they promote tumor progression by facilitating stromal desmoplasia.

The first detailed investigation of CD8⁺ tumor-infiltrating T cell differentiation in the hours after cells enter a tumor has yielded an unexpected twist. Naive T cells veer away from effector fate and enter the path towards exhaustion much earlier than expected.

We have used human-derived stem cells to generate various microglial states and investigate the function of human microglia in a scalable manner. We were able to model disease-associated microglia that replicated transcriptional signatures found in human tissue, and further developed a lentiviral transfer system to manipulate human microglial states in vitro.

Cytotoxic T cells fight pathogens and cancer by forming stereotyped cytotoxic immune synapses with infected or transformed target cells. We found that architectural changes in apoptotic target cells trigger the dissolution of immune synapses, providing a mechanistic basis for efficient synaptic turnover and serial killing.

Bronchus-associated lymphoid tissue (BALT), which develops in the lung during infancy before declining over childhood, supports localized immune reactions against airway infections in early life including the generation of germinal center-like B cells specific for respiratory pathogens.

LAG-3 is a T cell inhibitory receptor with a lot of promise as a target for immunotherapy, but considerable research will be needed to fully understand the nuances of this receptor and how best to target it, as outlined in this Perspective.

Susceptibility to respiratory pathogens is increased during early life, yet children can mount highly effective immune responses to novel pathogens in the absence of a fully developed immune system. We found that bronchus-associated lymphoid tissue (BALT) develops in the lungs early in life and supports germinal center formation and B cell differentiation to produce antibodies specific for respiratory pathogens, revealing a mechanism for immune protection in an as-yet-undeveloped immune system.

Delineation of the steps that lead to immune-related adverse effects indicates that checkpoint-mediated suppression of autoreactive T cells occurs within peripheral target tissues rather than at the point of lymph node activation.

The mechanisms by which T_H17 cells can either protect barrier tissues or initiate autoimmunity remain unknown. Here we identify the transcription factor EGR2 as a key determinant of T_H17 cell pathogenicity. EGR2 was found to govern T_H17 cell migration, regulate the expression of pathogenicity-associated genes, and facilitate the recruitment of other immune cells in the central nervous system.

Fibrosis, defined by the excess deposition of structural and matricellular proteins in the extracellular space, underlies tissue dysfunction in multiple chronic diseases. Bhattacharya and Ramachandran provide a review of recent advances in our understanding of the immunology of human fibrosis.