Biology subjects

Heeg, M.

Publications and source records attributed to Heeg, M..

4 recordsLinked to original sources

bioRxiv2026

FITdb, an Integrated Functional Immunogenomics and Transcriptomics Database

Genetic screens in immune cells enable the systematic interrogation of gene function at scale, uncovering key regulators of cell functions such as tumor cell killing and persistence. However, existing datasets typically focus on specific biological questions, employ targeted gene panels, are generated under diverse experimental conditions, and are not readily accessible, which together limit their integration and future usability. To address this, we developed the Functional Immunogenomics and Transcriptomics Database (FITdb), a freely accessible resource that harmonizes functional genomics datasets for the study of immune cell biology. FITdb currently integrates 43 independent functional genetics screens, including 32 pooled and 11 single-cell screens, spanning 20, 696 mouse genes and 22, 293 human genes across 199 immune cell types and conditions. All datasets are uniformly re-analyzed to enable cross-study comparisons. FITdb provides intuitive, gene-centric visualizations, detailed exploration of individual screens, and access to sgRNA-level data. Additionally, built-in tools such as "Compare MyGeneSet" and "Compare MyScreen" identify statistically significant overlaps between user-defined gene lists and functional gene sets in FITdb, and enable direct comparison of user-generated screening data with existing datasets, respectively. Together, FITdb provides a comprehensive, user-friendly platform for accelerating the discovery of immune regulatory programs. The database is freely available at https://fitdb.lji.org. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/741304v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@114d978org.highwire.dtl.DTLVardef@1d15d04org.highwire.dtl.DTLVardef@31c2f4org.highwire.dtl.DTLVardef@f63dfe_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

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↗

bioRxiv2025

Tertiary lymphoid structures support the development of allergen-specific progenitor CD4+ T cells

Tissue-resident memory CD4+ T cells (TRM) are key sentinels of the adaptive immune response that provide a rapid, robust inflammatory response upon reactivation in non-lymphoid tissues. While CD4+ TRM are highly protective during reinfections or tumor growth, they are also critical mediators of autoimmunity and allergic disease. Using transcriptional analysis and flow cytometry we profiled the heterogeneity of allergen-specific CD4+ TRM in the lungs following house dust mite exposure and observe two distinct populations of cells: a proinflammatory Th2 lineage and a progenitor TCF1+ lineage that can repopulate the Th2 branch. Confocal microscopy revealed that these two subsets occupied distinct anatomical niches in the inflamed lungs, with Th2 cells localized to the airways while TCF1+ cells localized within pulmonary tertiary lymphoid structures (TLS). Spatial transcriptomics affirmed the TLS as a tissue progenitor niche and highlight the transcriptional progression from progenitor to Th2 cell reflected in the TLS:airway axis. Manipulations to promote or ablate TLS development resulted in increased or decreased TCF1 expression among allergen-specific T cells, respectively. Finally, we identify the PD1 pathway as a critical signal localized to the TLS core and demonstrate that TCF1+ cells in the TLS are responsive to anti-PD1 treatment. Together, these data shape our understanding of tissue CD4+ T cell responses across space and time and highlight TLS as a critical therapeutic target that promotes the propagation of chronic inflammatory diseases.

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↗