Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.01.10.575073

Mapping the developmental trajectories of SAP-dependent innate-like gamma delta (γδ) T cells

Mistri, S. K.·Hilton, B. M.·Horrigan, K. J.·Andretta, E. S.·Savard, R.·Dienz, O.·Hampel, K. J.·Gerrard, D. L.·Rose, J. T.·Sidiropoulos, N.·Majumdar, D.·Boyson, J. E.
View original source ↗Export metadata ↓

Abstract

During thymic development, most {gamma}{delta} T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate {gamma}{delta} T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like {gamma}{delta} T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent {gamma}{delta} TCR repertoire. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+{gamma}{delta}T17 precursor population, and a significant increase in Cd4+Cd8+ Rorc+Ptcra+Rag1+ thymic {gamma}{delta} T cells. SAP-dependent diversion of embryonic day 17 thymic {gamma}{delta} T cell clonotypes into the {beta} T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered {gamma}{delta} TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent V{gamma}4 {gamma}{delta}T1 subset. Together, the data suggest that SAP-dependent {gamma}{delta}/{beta} T cell lineage commitment regulates {gamma}{delta} T cell developmental programming and shapes the {gamma}{delta} TCR repertoire. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/575073v3_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1d8b5aeorg.highwire.dtl.DTLVardef@7fd02dorg.highwire.dtl.DTLVardef@13c5c76org.highwire.dtl.DTLVardef@1da72b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

Source connections

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Mistri, S. K., Hilton, B. M., Horrigan, K. J., Andretta, E. S., Savard, R., Dienz, O., Hampel, K. J., Gerrard, D. L., Rose, J. T., Sidiropoulos, N., Majumdar, D., Boyson, J. E.. 2024-01-12. Mapping the developmental trajectories of SAP-dependent innate-like gamma delta (γδ) T cells. https://doi.org/10.1101/2024.01.10.575073

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↗