Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2023.11.07.565992

Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling

Grassmann, S.·Santosa, E. K.·Mujal, A. M.·Kim, H.·Fan, S. X.·Owyong, M.·Lau, C. M.·Sun, J. C.
View original source ↗Export metadata ↓

Abstract

Lymphocyte differentiation depends on activation via antigen and cytokines during the immune response to infection. How the timing and integration of these signals program the epigenetic and functional fate of these cells is not completely understood. In this study, we find that interleukin (IL)-12 signaling received by innate and adaptive lymphocytes has a context-dependent role for immune memory formation. In the absence of a preceding and/or sufficient antigen receptor signaling event, IL-12 impairs the adaptive expansion of cytotoxic lymphocytes. In contrast, sufficient antigen-receptor signaling redirects inflammatory cytokine signals to promote memory differentiation via cooperation of STAT4 and AP-1 transcription factors. By this crucial epigenetic mechanism, optimally equipped lymphocytes are selected for memory formation rather than a terminal effector cell fate. Whereas T cells are hardwired to be shielded from premature IL-12 signaling, NK cells rely on coincidental early antigen receptor signaling for adaptive responses. Together, step-wise integration of antigen and cytokine signaling optimizes both effector and memory differentiation, allowing for promiscuous recruitment into the acute immune response while promoting avidity maturation in memory populations of both innate and adaptive lymphocytes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/565992v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@192b969org.highwire.dtl.DTLVardef@1cabd1aorg.highwire.dtl.DTLVardef@145139aorg.highwire.dtl.DTLVardef@9faae_HPS_FORMAT_FIGEXP M_FIG C_FIG Key points- Adaptive NK cell responses rely on sequential integration of antigen and inflammatory signals. - Epigenetic redirection of STAT4 genomic binding promotes adaptive programming. - CD8+ T cell fate depends on antigen-dependent integration of inflammatory signaling. - STAT/AP-1 cooperation underlies step-wise integration of antigen and cytokine signaling in NK cells and CD8+ T cells.

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Grassmann, S., Santosa, E. K., Mujal, A. M., Kim, H., Fan, S. X., Owyong, M., Lau, C. M., Sun, J. C.. 2023-11-09. Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling. https://doi.org/10.1101/2023.11.07.565992

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Common viral infections seed regionally distinct resident memory T cells in the human CNS

T cells persist in the central nervous system (CNS) and can drive both protection and neurological disease. How these cells are organized in humans and what they recognize is largely unknown. Here, we profiled CD8 T cells across anatomically distinct CNS regions, obtained through on-site autopsies and temporal lobe resection surgeries, using single-cell RNA sequencing, paired T cell receptor sequencing, and DNA-barcoded tetramers. Resident memory T cells (TRM) specific for Epstein-Barr virus, cytomegalovirus, influenza A, and SARS-CoV-2 were identified across CNS compartments. Anatomical location was the strongest correlate of TRM cell state, with leptomeningeal cells adopting a cytokine-poised TRM program, whereas brain TRM cells were transcriptionally restrained. Cells of the same clonotype spanned tissues yet adopted local transcriptional states. Viral specificity added another layer of TRM heterogeneity with GZMK/GZMA-expressing EBV-specific populations and interferon-stimulated gene signatures in SARS-CoV-2 and Influenza A-specific cells. The human CNS thus harbors regionally distinct CD8+ TRM shaped by common viral exposures.

immunology↗
bioRxiv2026

A regulatory T cell signature provides a shared molecular basis for the therapeutic window of opportunity in rheumatic disease

Rheumatic diseases, including rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA), show distinct phenotypes yet respond to overlapping therapies, implicating shared immune mechanisms. In the Transimmunom cohort, we profiled peripheral blood from 240 individuals (47 healthy, 44 OA, 91 RA, 58 SpA) across deep immunophenotyping, immunoproteomics and Treg-Teff transcriptomics. Single-layer analyses revealed broader Treg than Teff remodeling, along with a shared pattern of reduced activated Tregs and expanded Helios+ Tregs across all diseases, alongside a decrease in functional Treg subpopulations, including CTLA4+ and CD45RA- Tregs. In RA specifically, LAG3+ Tregs were also expanded. Combining omics layers outperformed single-layer approaches for disease classification. Among individual layers, Treg transcriptomes were most discriminative, and integration uncovered disease-specific programs. Unsupervised clustering identified a cross-disease cluster independent of activity, treatment and age, mapping to early disease (<= years) and dominated by a Treg dysfunction-associated program. These results provide a biological rationale for the therapeutic "window of opportunity" concept and duration-stratified Treg-directed trials.

immunology↗
bioRxiv2026

Inhibitory Fc Receptor sets a time limit on macrophage response to IgG

Antibodies engage both activating Fc Receptors and the inhibitory receptor Fc{gamma}RIIB. Why macrophages need a dedicated inhibitory receptor rather than simply tuning activating receptor signaling is unclear. Using DNA-based chimeric receptors and in silico modeling, we independently controlled activating and inhibitory Fc Receptors. We found that Fc{gamma}RIIB imposed a time limit on macrophage phagocytosis and ERK signaling. The time limit is due to activating Fc Receptors converting PI(4,5)P2 to PI(3,4,5)P3, which is subsequently converted to PI(3,4)P2 by Fc{gamma}RIIB. This leads to a pulse of active signaling, which is sufficient for phagocytosis of small bacteria-sized targets but not phagocytosis of large targets and TNF secretion. Unlike engaging Fc{gamma}RIIB, reducing activating Fc Receptor signaling decreased initiation of phagocytosis, the speed of PI(3,4,5)P3 generation, and the amplitude of ERK signaling. Our results demonstrate that Fc{gamma}RIIB controls the duration of IgG signaling, while the activating Fc Receptors control sensitivity.

immunology↗