Biology subjects

Quon, S.

Publications and source records attributed to Quon, S..

5 recordsLinked to original sources

bioRxiv2026

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation to an exhausted state. In healthy tissues, tissue-resident memory T cells (TRM) maintain protection for years, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally-exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins in spite of functional proteasome activity. Enforced expression of these ligases by TIL preserved stem-like TCF1+ populations and improved anti-tumor function, whereas their knockout impaired TIL and altered T cell differentiation in acute infection. Sustained ligase expression rescued accumulation of unfolded proteins in TIL and improved immunotherapy outcome in preclinical models, highlighting the critical role of proteostasis in TIL function and identifying new avenues for advancing cancer immunotherapy.

immunology↗

bioRxiv2026

The CD8 immgenT framework as a universal reference of mouse CD8 Tαβ cell differentiation states

Mouse CD8+ T cell differentiation has been studied extensively in models of infections and tumors, yet no unified framework spans the full spectrum of immunological contexts. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD8+ T cells across >600 samples, spanning multiple perturbations, tissues, and timepoints. Twenty-one clusters across naive, effector, circulating memory, tissue-resident memory, progenitor-exhausted, and terminally-exhausted CD8+ T cell compartments emerged, with striking molecular convergence across acute and chronic infections, tumors, autoimmunity, aging, and homeostasis, illustrating that shared transcriptional states support protective or dysfunctional outcomes depending on developmental history and microenvironment. We validate immgenT as a comprehensive reference by integrating external datasets from conditions not represented in immgenT and by defining a flow cytometry panel spanning the CD8+ T cell landscape. Thus, immgenT-CD8 provides a molecular framework for harmonizing CD8+ T cell literature and clarifies relationships across diverse immune challenges.

immunology↗

bioRxiv2025

The long non-coding RNA Dreg1 is required for optimal ILC2 development

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells and innate lymphoid cells (ILC). As such, the levels and timing of Gata3 expression are critical for directing lineage fate decisions. The Gata3 locus has a complex and dynamic distal regulatory enhancer landscape. Recently we identified a non-coding RNA, Dreg1, located immediately upstream of the classic +280kb T/NK cell enhancer (Tce1). To test its function, we excised the Dreg1 locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCP) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of Gata3 in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express Dreg1 and showed alterations in the epigenetic landscape of the Dreg1 locus. Finally, we discovered that potential homologues of Dreg1 harboured in a syntenic enhancer of GATA3 are also highly expressed in human ILC2. Taken together we conclude that Dreg1 is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of Gata3 required for the optimal development of the ILC2 lineage.

immunology↗

bioRxiv2024

Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGF{beta} sources. Alterations in the cellular networks induced by loss of TGF{beta}RII expression revealed a model consistent with TGF{beta} promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

immunology↗

bioRxiv2023

Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

The differentiation of naive CD8+ cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naive, effector and memory virus-specific CD8+ T cells. We observed that the architecture of the naive CD8+ T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naive chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naive CD8+ T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naive chromatin state. One Sentence SummaryCD8+ T cell naivety is actively maintained by transcription factors that enforce a distinct, naive chromatin architecture. HighlightsO_LICD8+ T cell differentiation states are underscored by distinct chromatin looping architectures. C_LIO_LIChromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes. C_LIO_LIEffector and memory CTLs have similar genome architectures, explaining rapid memory recall. C_LIO_LICTL differentiation is restrained by BACH2 and SATB1, which enforce a naive loop architecture. C_LI

immunology↗