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-Il10 tm1Cgn (B6-Il10 −/− ) mice are partially resistant to colitis, whereas mice carrying the Cdcs1 C3Bir haplotype on chromosome 3, B6.Cg-Il10 tm1Cgn MMU3(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.