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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.
The DNA-binding domains of transcription factors have been well characterized, but whether their intrinsically disordered regions control cell fate is unclear. Here, the authors show the functional and mechanistic importance of an intrinsically disordered region of TCF-1 in T cell development.
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.
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.
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.
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.
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.
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 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.
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.
In inflammation, some regulatory T (Treg) cells lose FoxP3 expression and become exTreg cells. Ley and colleagues mapped mouse Treg and exTreg cell transcriptomes to a human peripheral blood mononuclear cell single-cell RNA-sequencing dataset with surface markers (CITE-seq) and identify human exTreg cells as cytotoxic CD4+ T cells.
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’.