Volume 24 Issue 9, September 2023

The effects of climate change driven by human activity are now part of the daily news cycle, and time is running out for decisive action.

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.

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.

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.

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.

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.

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.

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.

To kill target cells, cytotoxic T lymphocytes (CTLs) form an immune synapse (IS) to elicit cell death and the IS then dissolves to allow for CTL serial killing. Huse et al. find that IS dissolution occurs concomitantly with cytoskeletal contraction of apoptotic targets and this is both necessary and sufficient for CTL dissociation

DeNardo and colleagues show that tissue-resident macrophages (TRMs) have a protective role during pancreas inflammation by triggering the activation of fibroblasts, but that TRM-driven fibrosis drives pancreas cancer pathogenesis.

Runx family proteins direct lineage-fate decisions in multiple cell types. Here, Rothenberg and colleagues show how limited Runx protein abundance dictates T cell lineage developmental kinetics through competition for binding by its protein interaction partners.

Here, the authors show that short-term consumption of energy-dense diets deficient in fiber, similar to eating patterns for many people today, results in a transient depression of the mucosal and systemic immune systems such that susceptibility to bacterial infection is increased.

As the Plasmodium species that cause malaria replicate in the liver, Heath and colleagues designed mRNA vaccines to limit infection by inducing liver-resident memory T cells. Efficacy was observed in mice, including in hosts with previous blood-stage infection.

Chimeric antigen receptor (CAR)-T cells may become exhausted, non-functional or deplete their target cells of antigen, limiting their efficacy. Chen and colleagues fuse the CTLA-4 cytoplasmic tail to a CAR, which compromises trogocytosis and increases the functional capacity of CAR-T cells.

Thomas and colleagues examine preinfection baseline parameters of cellular and serologic immunity. Their findings collectively show that peripheral cell composition provides better correlates of immune protection from symptomatic influenza infection than vaccination, demographics or serology alone.

Rudloff et al. examine the kinetics of CD8⁺ T cell dysfunction/exhaustion. Tumor-specific CD8⁺ T cells in the tumor environment exhibit epigenetic modifications within hours, before cell division. The findings suggest a temporal relationship between tumor antigen exposure, chromatin remodeling and dysfunction ‘imprinting’.

Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.

Sen et al. provide in-depth temporal multi-omic analyses with single-cell RNA-sequencing (scRNA-seq) profiles of nuclear factor kappa B (NF-κB)-regulated gene expression in B cells upon B cell receptor (BCR) activation. Their findings reveal distinct kinetic patterns of gene expression mediated by RelA and Rel and functional antagonism between the closely related NF-κB subunits.

Garner et al. analyzed the single-cell transcriptome and TCR repertoire of matched blood and liver, and resting and activated, human MAIT cells. They identify donor-specific TCR repertoires shared across tissues and a transcriptome that is largely homogeneous at rest, but highly adaptive to different tissue and stimulation environments.

Streets, Yosef, Robey and colleagues use multiomics analysis to generate a comprehensive timeline of the CD4⁺ and CD8⁺ T cell lineage commitment and identify sequential waves of TCR signaling that first initiate CD4⁺ T cell lineage differentiation and then CD8⁺ T cells lineage specification.