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Analysis of Cdcs1 colitogenic effects in the hematopoietic compartment reveals distinct microbiome interaction and a new subcongenic interval active in T cells

Abstract

Disease activity in Interleukin-10-deficient (Il10−/−) mice, a model for IBD, depends on genetic background and microbiome composition. B6.129P2/JZtm-Il10tm1Cgn (B6-Il10−/−) mice are partially resistant to colitis, whereas mice carrying the Cdcs1C3Bir haplotype on chromosome 3, B6.Cg-Il10tm1CgnMMU3(D3Mit11-D3Mit348)/JZtm (BC-R3-Il10−/−), are susceptible. This study was performed to clarify Cdcs1 and candidate gene effects on the colitogenic potential of hematopoietic cells using bone marrow (BM) and T-cell transfer models. Acute and chronic graft versus host reaction was excluded by high-density genotyping, in vitro and in vivo approaches. BM-chimeras were created with animals housed in two barriers (I and II) with distinct microbiota composition as identified by sequencing. BM-chimeras of all groups developed comparable moderate-to-severe colitis in Barrier I, however, in Barrier II only recipients of BC-R3-Il10−/− BM. Subsequent adoptive T cell transfers pointed to a new subcongenic interval within Cdcs1 affecting their colitogenic potential. Transfers excluded Larp7 and Alpk1 but highlighted Ifi44 as potential candidate genes. In this model-system, colitis development after cell transfer heavily depends on microbiome, though Cdcs1 acts mainly independently in hematopoietic cells. A new subcongenic interval, provisionally named Cdcs1.4, modifies colitogenic T cell function. Within this locus, Ifi44 represents an important candidate gene for colitis expression.

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Acknowledgements

This work was supported by the Hannover Biomedical Research School (HBRS), the Center for Infection Biology (ZIB), and a stipend to Inga Brüsch. Marius Vital and Dietmar H. Pieper were supported by iMed, the Helmholtz Association’s Initiative on Personalized Medicine. We thank Britta Trautewig, Anna Smoczek, Andrea Liese, Anja Siebert, Silke Kahl, Iris Plumeier and Elena Wiebe for providing excellent technical assistance.

Author information

I.B., M.Bue., P.M., M.Ba. and A.B. conceived and designed the experiments and wrote the manuscript. I.B., P.M., K.S., S.B. and M.Bue. performed the experiments and analyzed the data. I.B. and P.M. contributed equally to the work. M.V. and D.P. performed and analyzed microbiome experiments. M.M. performed MRI evaluation. S.G. provided support for the evaluation of the histology. J.H. performed and analyzed MLC experiments. D.W. performed genetic data confirmation. M.Bue. and A.B. supervised the work and contributed equally.

Correspondence to André Bleich.

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