A-T.51: Histone Deacetylases 1 and 2 Regulate Intestinal T Cell Subsets and are Essential for Th1/Th17 Immunity against Citrobacter rodentium
Authors
Phuc Huu Tran
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Rafael de Freitas e Silva
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Aruana Fagundes Fiuza Hansel Fröse
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Moritz Madern
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Monika Waldherr
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Teresa Preglej
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Birgit Niederreiter
Medical University of Vienna, Department of Internal Medicine III, Division of Rheumatology.
Caroline Lassnig
University of Veterinary Medicine Vienna, Centre of Biological Sciences
Sara Catarina da Silva Miranda
University of Veterinary Medicine Vienna, Centre of Biological Sciences
Sandra Högler
University of Veterinary Medicine Vienna, Unit of Laboratory Animal Pathology
Thomas Krausgruber
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Christoph Bock
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Philipp Starkl
Medical University of Vienna, Department of Medicine I, Research Division of Infection Biology
Sylvia Knapp
Medical University of Vienna, Department of Medicine I, Research Division of Infection Biology
Birgit Strobl
University of Veterinary Medicine Vienna, Centre of Biological Sciences
Michael Bonelli
Medical University of Vienna, Department of Internal Medicine III, Division of Rheumatology
Wilfried Ellmeier
Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Division of Immunobiology, Institute of Immunology
Keywords
Intestinal T cells, Citrobacter rodentium, CD4 CTL, epigenetic regulation, HDAC1, HDAC2
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The gastrointestinal tract contains diverse conventional and unconventional T cell populations, including CD4+ cytotoxic T lymphocytes (CTLs), whose regulatory programs remain incompletely understood. To characterize transcriptional and regulatory changes underlying intestinal T cell heterogeneity, focusing on the epigenetic regulators HDAC1 and HDAC2, we performed single-cell RNA sequencing (scRNA-seq) combined with transcription factor activity inference across small intestinal intraepithelial lymphocytes (SI-IEL), lamina propria (SI-LP), and colonic T cells from mice lacking both Hdac1 alleles and one Hdac2 allele (HDAC1cKO-HDAC2HET). Single-cell transcriptomic analysis revealed compartment-specific effects of HDAC1/2 loss, with SI-IELs showing the strongest transcriptional alterations. Clustering and differential expression analyses identified an expansion of RUNX3high CD4-CD8a+b low subsets, including populations with mixed CD4+ lineage transcriptional features. TF activity inference supported a shift toward cytotoxic regulatory programs in HDAC1/2-deficient cells. Across intestinal tissues, CD4+ lineage cells displayed increased cytotoxic gene signatures, but reduced IL-17A-associated expression in the colon. During Citrobacter rodentium infection, HDAC1cKO-HDAC2HET mice showed impaired induction of protective Th1/Th17 programs, accompanied by increased representation of cytotoxic CD4+ CTLs. These results indicate that HDAC1 and HDAC2 regulate transcriptional programs restraining CD4+ T cell differentiation to CTLs, maintaining T cell homeostasis and effector function during bacterial infection. Additionally, we highlight the utility of single-cell transcriptomics and TF activity analysis for resolving functional heterogeneity in intestinal immune cells.
Co-authors: Phuc Huu Tran, Rafael de Freitas E Silva, Moritz Madern, Monika Waldherr, Teresa Preglej, Birgit Niederreiter, Caroline Lassnig, Sara Catarina Da Silva Miranda, Sandra Högler, Thomas Krausgruber, Christoph Bock, Philipp Starkl, Sylvia Knapp, Birgit Strobl, Michael Bonelli, Wilfried Ellmeier
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