Taras Kreslavsky

The microprotein p11 ( S100A10 ) is a ubiquitously expressed molecular scaffold that is known to be required for behavioral responses to certain antidepressants, presumably through its effect on G protein–coupled receptor (GPCR)–mediated signaling. Here, we demonstrate that p11 recruitment to GPCRs is promoted by an active receptor conformation. Furthermore, by mapping the GPCR-p11 interactome using a multiplexed suspension bead array (SBA) of 211 receptors, we identified more than two dozen high-confidence physical interactors across diverse GPCR signaling families. We define the functional significance of these interactions by focusing on a novel SBA screening hit, the protease-activated receptor 2 (PAR2). Transcriptomic fingerprinting and signaling assays in p11-knockout cells reveal that p11 acts as an amplifier of endogenous PAR2 signaling. PAR2 and p11 are specifically coexpressed in vivo in a subset of sensory neurons, and p11-deficient mice exhibit a blunted PAR2-mediated inflammatory response. Our results establish p11 as a widespread, activity-dependent modulator of GPCR-mediated signaling outcomes across diverse physiological processes.

Of the three classes of lymphocytes that constitute the adaptive immune system, γδT cells are the only class for which the principles of antigen recognition remain enigmatic. Although endogenous γδT cell antigen receptor (γδTCR) ligands are thought to regulate γδT cell development, their identities are largely elusive. Here, we identified the interleukin 17 receptor A chain (IL17RA) as a γδTCR ligand that drove the differentiation of Vδ7 ⁺ γδT cells with a T helper 1 (T _H 1)–like effector program in mice. IL17RA promoted this differentiation through an interaction involving germline-encoded regions of the Vδ7 chain, enabling the selection of cells with a diverse CDR3 repertoire and thus acting as a nonclonotypic γδTCR ligand. Together with the nonclonotypic mode of γδTCR engagement by butyrophilins, these results suggest that such interactions represent a general biological mechanism shaping the γδT cell compartment.

Monocytes populate tissues when local niches are depleted of tissue-resident macrophages, yet the tissue-derived signals controlling monocyte-to-macrophage differentiation are largely undefined. Here, we discovered that the oxysterol receptor GPR183 positions monocytes to sense niche signals that induce lung macrophage differentiation. We found that interstitial macrophages that continuously turn over express the oxysterol receptor GPR183, whereas alveolar macrophages that derive from embryonic progenitors and slowly turn over did not. Models of conditional tissue-resident macrophage depletion showed that newcomer monocyte-derived macrophages expressed GPR183 along their differentiation trajectory. Recruited GPR183+ monocytes interacted with fibroblasts and lack of GPR183 caused defective lung macrophage differentiation. Single-cell RNA analysis over time identified lung fibroblasts as the source of the GPR183 ligand 7α,25-dihydroxycholesterol in the empty niche. Our findings identify oxysterols as instructive signals for tissue-resident macrophage development from monocytes.

The distinctive feature of the adaptive immune system is its ability to generate immunological memory that can provide defense against subsequent infections. In the case of antibody-mediated immune responses, this memory comes in two cellular forms: plasma cells (PCs) and memory B cells (MBCs). PCs protect against reinfection by constitutively producing antibodies. The presence of a diverse pool of MBCs, which can expand and differentiate into PCs in secondary immune responses, is thought to be particularly important for defense against new pathogen variants. Recent studies have shown that the MBC compartment is far more heterogeneous than previously anticipated. This heterogeneity, among other factors, is shaped by their developmental pathway (germinal center (GC) vs non-GC-derived MBCs), the duration and strength of antigenic stimulation, anatomical and microanatomical localization, and the timing of generation in ontogeny. Combinations of these “layers” of MBC identities can define MBCs’ properties and their fate in recall responses. Here, we review the mechanisms underlying MBC differentiation, maintenance, and reactivation and explore how the layered identity of MBCs contributes to the functions of these cells.

The thymus exhibits constitutive activation of nearly all major inflammatory pathways, including sterile MyD88‐dependent signaling and interferon production by mTECs, the presence of cellular and molecular components of type 1, type 2, and type 3 responses, as well as sustained B cell activation. The reasons for the existence of such a complex constitutively active inflammatory network at the site of T cell development—where the initial pathogen encounter is unlikely—have remained enigmatic. We propose that this inflammatory thymic ‘ecosystem’ has evolved to promote immunological tolerance to ‘inflammatory self’—endogenous molecules absent from most peripheral tissues at steady state but upregulated during pathogen invasion. The spatial and temporal overlap with pathogen presence makes the discrimination of the inflammatory self from pathogen‐derived molecules a unique challenge for the adaptive immune system. The frequent occurrence of diseases associated with autoantibodies against proinflammatory cytokines underscores the persistent risk of these molecules being misidentified as foreign. Their abundant representation in the thymus, therefore, is likely to be critical for maintaining tolerance. This review explores current insights into the thymic inflammatory network, its cellular and molecular constituents, and their role in the induction of T cell tolerance.

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8⁺ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8⁺ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.

Genetic and experimental evidence suggests that Alzheimer’s disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, sc/nRNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as DLAMs. Using macrophage sc/nRNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40/41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.

Helicobacter pylori colonization of the gastric niche can persist for years in asymptomatic individuals. To deeply characterize the host–microbiota environment in H . pylori –infected (HPI) stomachs, we collected human gastric tissues and performed metagenomic sequencing, single-cell RNA-Seq (scRNA-Seq), flow cytometry, and fluorescent microscopy. HPI asymptomatic individuals had dramatic changes in the composition of gastric microbiome and immune cells compared with noninfected individuals. Metagenomic analysis uncovered pathway alterations related to metabolism and immune response. scRNA-Seq and flow cytometry data revealed that, in contrast to murine stomachs, ILC2s are virtually absent in the human gastric mucosa, whereas ILC3s are the dominant population. Specifically, proportion of NKp44 ⁺ ILC3s out of total ILCs were highly increased in the gastric mucosa of asymptomatic HPI individuals, and correlated with the abundance of selected microbial taxa. In addition, CD11c ⁺ myeloid cells and activated CD4 ⁺ T cells and B cells were expanded in HPI individuals. B cells of HPI individuals acquired an activated phenotype and progressed into a highly proliferating germinal-center stage and plasmablast maturation, which correlated with the presence of tertiary lymphoid structures within the gastric lamina propria. Our study provides a comprehensive atlas of the gastric mucosa–associated microbiome and immune cell landscape when comparing asymptomatic HPI and uninfected individuals.