Immunology

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function1. To study these ‘kiss-and-run’ interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)2, an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8+ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell–cell interactions across multiple biological systems. A paper reports the development of a universal tool for studying cellular interactions in biological systems, and demonstrates its coupling with single-cell transcriptomics methods to provide insights into the biology of the interactions.

The human transferrin receptor (TfR) identified as an alternative receptor for SARS-CoV-2 infection in human cells. Human TfR, which is abundantly expressed…

CD4 T cells are the the best ?

Summary. Complex cellular interactions between the immune system and cancer can impact tumour development, growth, and progression. T cells play a key role in t

Summary. Basophils are the rarest leukocytes, but they have essential roles in protection against helminths, allergic disorders, autoimmune diseases, and some c

The Epstein-Barr virus (EBV) is a ubiquitous human pathogen linked to various diseases, including infectious mononucleosis and multiple types of cancer

#Immunity | #Infection | #Cancer | #Immunotherapy | #Bregs | #Tregs | #MDSCs | Mechanisms Underlying #Immunosuppression by #Regulatory Cells | Breaking OPEN…

B cell and T cell receptor repertoires compose the adaptive immune receptor repertoire (AIRR) of an individual. The AIRR is a unique collection of antigen-specific receptors that drives adaptive immune responses, which in turn is imprinted in each individual AIRR. This supports the concept that the AIRR could determine disease outcomes, for example in autoimmunity, infectious disease and cancer. AIRR analysis could therefore assist the diagnosis, prognosis and treatment of human diseases towards personalized medicine. High-throughput sequencing, high-dimensional statistical analysis, computational structural biology and machine learning are currently employed to study the shaping and dynamics of the AIRR as a function of time and antigenic challenges. This Primer provides an overview of concepts and state-of-the-art methods that underlie experimental and computational AIRR analysis and illustrates the diversity of relevant applications. The Primer also addresses some of the outstanding challenges in AIRR analysis, such as sampling, sequencing depth, experimental variations and computational biases, while discussing prospects of future AIRR analysis applications for understanding and predicting adaptive immune responses. The adaptive immune receptor repertoire (AIRR) drives adaptive immune responses, which could determine disease outcomes, infectious disease and cancer. Mhanna, Bashour et al. outline the approaches and challenges in AIRR analysis, as well as future developments towards predicting adaptive immune responses.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor and plays a critical role in the immune response. TREM-1 activation leads to the production and release of proinflammatory cytokines, chemokines, as well as its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). Because patients with sepsis and septic shock show elevated sTREM-1 levels, TREM-1 has attracted attention as an important contributor to the inadequate immune response in this often-deadly condition. Since 2001, when the first blockade of TREM-1 in sepsis was performed, many potential TREM-1 inhibitors have been established in animal models. However, only one of them, nangibotide, has entered clinical trials, which have yielded promising data for future treatment of sepsis, septic shock, and other inflammatory disease such as COVID-19. This review discusses the TREM-1 pathway and important ligands, and highlights the development of novel inhibitors as well as their clinical potential for targeted treatment of various inflammatory conditions.

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated. In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period. Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05). Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Summary. There is an intriguing dichotomy in the function of cytokine interleukin-15—at low levels, it is required for the homeostasis of the immune system, yet

Inflammasomes are supramolecular complexes that form in the cytosol in response to pathogen-associated and damage-associated stimuli, as well as other danger signals that perturb cellular homoeostasis, resulting in host defence responses in the form of cytokine release and programmed cell death (pyroptosis). Inflammasome activity is closely associated with numerous human disorders, including rare genetic syndromes of autoinflammation, cardiovascular diseases, neurodegeneration and cancer. In recent years, a range of inflammasome components and their functions have been discovered, contributing to our knowledge of the overall machinery. Here, we review the latest advances in inflammasome biology from the perspective of structural and mechanistic studies. We focus on the most well-studied components of the canonical inflammasome — NAIP–NLRC4, NLRP3, NLRP1, CARD8 and caspase-1 — as well as caspase-4, caspase-5 and caspase-11 of the noncanonical inflammasome, and the inflammasome effectors GSDMD and NINJ1. These structural studies reveal important insights into how inflammasomes are assembled and regulated, and how they elicit the release of IL-1 family cytokines and induce membrane rupture in pyroptosis. This Review highlights new insights into the biology of inflammasomes from the perspective of structural and mechanistic studies, revealing how the supramolecular complexes that activate inflammatory caspases are assembled and regulated, to induce cytokine maturation and release, as well as pyroptotic cell death.

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C–X–C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions. Here, the authors characterize two distinct Treg cell populations in the visceral adipose tissue of lean and high-fat diet-fed mice. ST2+ Treg cells are dominant in male mice and are transcriptionally driven by GATA3 and PPARγ, regulators that limit the differentiation of the more female-dominant population of CXCR3+ Treg cells that are T-bet dependent. Functional distinctions are also evident in glucose tolerance and adipose inflammation.

TCR signaling (signal 1) induces STAT3 phosphorylation through Lck/Fyn and, synergistically with cytokine signal (signal 3), induces optimal STAT3 phosphorylati