Reviews & Analysis

On 20–23 June 2023, the 10th International γδ T cell conference was held in Lisbon, Portugal, bringing together basic, translational and clinical researchers studying γδ T cells in health and disease.

After vaccination, spike-specific CD8⁺ T cells play an important part in the immediate immune response to breakthrough SARS-CoV-2 infection, whereas the B cell and neutralizing antibody responses come into effect 2 weeks after infection.

That regulatory T cells can change their phenotypes has been shown in mouse models of atherosclerosis and other autoimmune diseases. We suspected that this phenomenon would also be true in humans. To test this hypothesis, we developed a strategy to identify human ‘exT_reg’ cells and found that they express a cytotoxic transcriptome.

We show that multivalent epitope display on the surface of viral-sized particles functions as a ‘stand-alone’ danger signal by evading inhibitory pathways to trigger a unique mode of B cell receptor signaling. The activation, survival and proliferation of B cells stimulated with particulate antigen is highly enhanced compared with those stimulated with soluble antigen, and does not require co-stimulation from T cells.

Many transcription factors contain intrinsically disordered regions whose functions are not well characterized. An intrinsically disordered region in TCF-1 has now been found to have an essential function in coordinating T cell lineage commitment.

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.