Abstract Background Crohn’s disease (CD) is thought to result from a complex interplay between genetic susceptibility, environmental factors, gut dysbiosis, and aberrant immune activation, in which T helper (CD4+) cells play a central pathogenic role. This multifactorial nature makes it challenging to disentangle the contribution of each component to disease pathogenesis and pathophysiology, especially in clinical studies. Twin studies provide an opportunity to partially overcome these limitations, as twins share a nearly identical genetic background and similar early-life environmental exposures. Furthermore, healthy co-twins of CD-discordant twins are at increased risk of CD development, providing a powerful framework to investigate early or preclinical disease-associated alterations. Methods In this study, samples from the IBD-TWIN cohort1 were used to study CD4+ T cells in CD. Several CD4+ T cell subsets were isolated from peripheral blood mononuclear cells (PBMCs) of CD-concordant and discordant monozygotic twin pairs and unrelated healthy controls using fluorescence-activated cell sorting (FACS), followed by single cell immune profiling, bulk RNA sequencing, and DNA methylation profiling. Sorted subsets included naïve (CD45RA+CCR7+) and gut-homing (integrin β7+) memory (CD45RA-) CD4+ T cells. Results CD4+ memory T cells with gut-homing capacity were found to be transcriptionally different between CD patients and unrelated healthy controls. Interestingly, there were no differences between the transcriptomes of healthy co-twins and CD patients, suggesting that healthy co-twins have a CD-like CD4+ T cell transcriptome resembling that of their CD co-twin. Comparable findings were obtained for DNA methylation profiles. Strikingly, these CD-like signatures were even identified in naïve CD4+ T cells of healthy co-twins. Transcriptional differences were associated with pathways such as apoptosis, T cell activation and proliferation, and TCR signalling and were not highly specific to certain subsets of naïve or memory CD4+ T cells. Moreover, public T cell clones with identical α-and β-chain CDR3 nucleotide sequences were present within twin pairs, while absent in other comparisons. Conclusion The findings of this study suggest that genetically predisposed healthy co-twins present with a CD-like CD4+ T cell transcriptome and DNA methylation profile. This might either point towards skewing of the CD4+ T cell compartment to a CD-like phenotype, possibly preceding CD development, or reflect the shared genetic and environmental background. References: 1.Brand, E. C., Klaassen, M. A., Gacesa, R., Vila, A. V., Ghosh, H., De Zoete, M. R.,... 160(6):1970-1985. Conflict of interest: Kusters, Thom: No conflict of interest Saager, Elise: No conflict of interest Holland van den Noort, Leonie: No conflict of interest Brand, Eelco: ECB was co-applicant on an unrestricted Investigator Initiated Research Grant of Pfizer van den Broek, Theo: No conflict of interest Oldenburg, Bas: Unrestricted grants: Abbvie, Takeda, Pfizer, Galapagos Advisory boards: Abbvie, Takeda, Pfizer, Lilly, Galapagos, Janssen Yermanos, Alex: No conflict of interest van Wijk, Femke: Prof. F. van Wijk has been a speaker and/or consultant for Janssen, Johnson & Johnson, and Takeda and has received grants from Regeneron Pharmaceuticals, Leo Pharma, Sanofi, BMS, Galapagos, and Takeda. Bakker, Sophie: No conflicts of interest
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