Year: 2026
Type: preprint
Abstract: CTLA-4 (haplo)insufficiency displays incomplete penetrance and phenotypic heterogeneity, indicating the involvement of additional disease modifiers beyond the genetic defect. Microbiome analyses reveal a positive association between disease severity and intestinal dysbiosis, highlighting the microbiome as a critical contributor. To investigate this relationship mechanistically, we generated Ctla4⁺ / ⁻ wildlings harboring a natural microbiota. Unlike specific pathogen free (SPF) counterparts, which remain healthy, Ctla4⁺ / ⁻ wildlings spontaneously develop disease phenotypes resembling human CTLA-4 haploinsufficiency. Disease onset is followed by reduced microbial diversity and expansion of pathobionts. Integrative immunophenotyping shows that the natural microbiota synergizes with Ctla4 haploinsufficiency to reshape innate and adaptive immune compartments, generating a sustained pro-inflammatory milieu and reduced CTLA-4 expression in the cecum. Furthermore, microbiota-derived metabolites promote inflammatory cytokine production in both murine and human primary T cells via NF-κB activation. Collectively, Ctla4⁺ / ⁻ wildlings constitute an effective model for dissecting microbiome–immune crosstalk in CTLA-4 (haplo)insufficiency and for exploring therapeutic strategies.
Authors: Bei Zhao, Lara Stopp, Pavaret Sivapornnukul, Simon Lagies, Kun D. Huang, Till Robin Lesker, Virginia Andreani, Rabina Giri, Pavla Mrovecova, Wiebke Schifferdecker, Angelika Hofmann, Katja Gräwe, Luis Braun, Jakob Begun, Christoph Schell, Stephan P. Rosshart, Bernd Kammerer, Till Strowig, Bodo Grimbacher
Institutions: University of Freiburg, University Medical Center Freiburg, Helmholtz Centre for Infection Research, The University of Queensland, Mater Research, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Medizinische Hochschule Hannover, Centre for Individualised Infection Medicine, German Center for Infection Research
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1078610655, G1284162446, G1360757276, G1501190094, G207631012, Funktion und Bedeutung des Transkriptionsfaktors ZNF341 in Lymphozyten, G2226533489, G24073139, G259924242, G2837854789, Zellsortiersystem, Morphofunktionelle Dekodierung von ZellMatrix Interaktionen in nephropathologischen und uropathologischen Erkrankungen, G3523822304, G3544412130, G3912926014, G4206229305, EXC 2155: RESIST Resolving Infection Susceptibility, Entdeckung neuartiger Behandlungsmethoden global relevanter Erkrankungen unter Zuhilfenahme des translationalen Wildling Models und komplementärer, hochdimensionaler Verfahren, TRR 359: Perinatale Entwicklung der ImmunzellTopologie (PILOT), SFB 1160: Immunpathologie aufgrund eingeschränkter Immunreaktionen (IMPATH), G4796096790, G4866485077, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, G5171826047, G5186833673, G568792620, G5976804734, G6000535164, G6160902421, G6351858858, G6952166915, G7084865219, G7235534959, G7399536025, G7408295208, G7436303907, G7833425038, GAIN - Deutsches Netzwerk für die Erforschung und Therapieoptimierung von Patienten mit genetischen Multi-Organ-Autoimmunerkrankungen: Koordination, Patientenregister, Forschung zu verschiedenen Immundefekten (CTLA4, FKB1, STAT3-GOF), epidemiologische Studie zur Verbesserung der Versorgung und Lebensqualität, G8535061057
OpenAlex ID: W7203651964