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Through in vivo tracking of tumor-specific CD8⁺ T cells in response to immunotherapy in mice, Barboy et al. characterize the tumor response to anti-PD-1 therapy and optimize a combination treatment with anti-4-1BB agonist.

Anandasabapathy and colleagues show that the inhibitory receptor PD-1 impacts the specification of tissue-resident memory T cells in the skin.

Proseg is a segmentation approach for single-cell spatially resolved transcriptomics data that uses unsupervised probabilistic modeling of the spatial distribution of transcripts to accurately segment cells without the need for multimodal staining.

Mass cytometry is shaping up to be a transformative technology for the description of immunological cell populations. In their Commentary, however, Newell and Cheng report that with great power comes great complexity and concomitant challenges for data analysis and visualization.

The detection of multiple and often rare T cell specificities is crucial for understanding and therapeutically manipulating T cell responses. In this Perspective article, Daviset al. summarize the latest advances in peptide–MHC multimer technology that have rendered peptide–MHC multimers a valuable tool in both basic and clinical T cell research.

An approach involving combinatorial peptide–MHC tetramer staining and mass cytometry allows simultaneous screening of over 100 T-cell specificities in a single human blood sample.

A benchmarking analysis on single-cell RNA-seq and mass cytometry data reveals the best-performing technique for dimensionality reduction.

Myeloid cells show great phenotypic and functional diversity. Newell and colleagues use mass cytometry with a panel of 38 mouse myeloid markers to describe myeloid cell phenotypic diversity in unprecedented depth within eight different tissues.

Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.

Most MAIT cell response to infection studies are of mice. Here the authors characterize MAIT cell population responses to Salmonella Paratyphi A infection of 25 human volunteers using TCR clonotype analysis and mass cytometry of pre-infection matched to post-infection samples.

Human lung and colorectal tumours contain a population of tumour-infiltrating lymphocytes that are specific for tumour-unrelated antigens and, unlike tumour-antigen-specific tumour-infiltrating lymphocytes, do not express CD39.

Long COVID or post-acute sequelae of SARS-CoV-2 is defined by persisting chronic symptoms following acute SARS-CoV-2 infection but represent an aetiologically diverse group of disorders. Here authors identify molecularly distinct subtypes, including a form with persistent inflammation, via longitudinal analysis of serum proteome.

BCG revaccination of adolescents has been shown to provide some protection against sustained infection with Mycobacterium tuberculosis. Here, using intracellular cytokine staining and CITE-Seq, the authors identify several effector memory CD4⁺ T cell populations in adolescents revaccinated with BCG that can aid the search for correlates of protection.

Combinations of fluorescently labeled peptide–major histocompatability (pMHC) tetramers are used to simultaneously detect T cells with multiple antigen specificities from human blood samples. Also in this issue, Hadrup et al. present a very similar combinatorial encoding approach.

Davis and Newell explain how cytometry, and single-cell and sequencing methodologies can be used to characterize human T-cell responses in health and disease.

Ginhoux and colleagues show that the priming of mouse hematopoietic progenitor cells toward the pDC lineage occurs at the common lymphoid progenitor stage.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells, abundant in mucosal tissues, blood and liver. Here, using T-cell cloning and deep sequencing, Lepore et al. analyse the T-cell receptorβ repertoire of MAIT cells and further characterize function and tissue distribution of two semi-invariant subsets of these cells.

Severe malaria can be associated with respiratory complications. Here, the authors show that malaria-associated pulmonary vascular damage is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8⁺ T cells induced during infection.

Typhoidal Salmonella is a major pathogen, but there is still a lack of knowledge about suitable vaccine antigens. Cerundolo and colleagues deep-phenotype bacteria-specific CD4⁺ T cells of Salmonella-infected volunteers to define cross-reactive and serovar-specific responses.

Classical human dendritic cells (cDCs) are rare sentinel cells specialized in regulating adaptive immunity. Here, the authors show that expression of membrane bound FLT3L, along with stem cell factor (SCF) and CXCL12 in stromal cells induces specification of pre/AS-DCs, type 1 and type2 cDC from haematopoietic stem cells.

The identity of stem-cell memory progenitor cells has been unclear. Lugli and colleagues use high-dimensional approaches to identify two new progenitor populations of human T cells—one giving rise to a functional lineage, the other to an exhausted-like one.

Complementary single-cell approaches show that a population of regulatory T cells co-expressing ICOS and IL-1 receptor type 1 is highly enriched in tumours but not in site-matched inflamed non-malignant tissue.

Tetramers of peptide and major histocompatibility complex (pMHC) are very useful for the detection of specific T cell antigen receptors; however, they have several drawbacks. Davis and colleagues describe photocrosslinkable pMHC monomers with several important advantages and use these to probe the immunological synapse.

A combination of an FFPE nuclei preparation protocol and a probe-based transcriptomic profiling technique enables snRNA-seq characterization of archival human FFPE tissues, holding promise for retrospective studies involving aged clinical cohorts.

The progenitor stage of commitment toward the conventional dendritic cell subsets and the transcriptional networks that control it remain poorly understood. Two articles from Ginhoux and colleagues and Murphy and colleagues offer insight into these processes.

T lymphocytes, which are an integral part of most adaptive immune responses, recognize foreign antigens through the binding of antigenic peptide–major histocompatibility complex (pMHC) molecules on other cells to specific T-cell antigen receptors (TCRs). Using single-molecule microscopy and fluorescence resonance energy transfer, the kinetics of TCR–pMHC binding are now measured in situ, revealing accelerated kinetics and increased affinity when compared with solution measurements.

Prenatal immune suppression is regulated by fetal arginase-2-expressing dendritic cells which respond normally to toll-like receptor stimulation but, in contrast to adult dendritic cells, induce regulatory T cells and repress TNF-α secretion by effector T cells.

This Review provides an overview of existing studies using single-cell technologies to provide insights over the immune responses and molecular mechanisms at work in COVID-19.

This Perspective discusses recent technological developments in flow cytometry and DNA sequencing that enable the interrogation of T-cell specificities in infection, cancer and autoimmunity to inform disease development and treatment.

Diversity of T cells & asthma subtypes.