Total CD3 T Cells Are Necessary and Sufficient to Induce Colitis in Immunodeficient Mice With Dendritic Cell-Specific Deletion of TGFbR2: A Novel IBD Model to Study CD4 and CD8 T-Cell Interaction

Background: Inflammatory bowel disease (IBD) is a multifactorial disorder, with the innate and adaptive immune cells contributing to disease initiation and progression. However, the intricate cross-talk between immune cell lineages remains incompletely understood. The role of CD8(+) T cells in IBD pathogenesis has been understudied, largely due to the lack of appropriate models. Methods: We previously reported spontaneous colitis in mice with impaired TGF beta signaling due to dendritic cell-specific knockout of TGFbR2 (TGF beta R2(Delta DC)). Here, we demonstrate that crossing TGF beta R2(Delta DC) mice with a Rag1(-/-) background eliminates all symptoms of colitis and that adoptive transfer of unfractionated CD3(+) splenocytes is sufficient to induce progressive colitis in Rag1(-/-)TGF beta R2(Delta DC) mice. Results: Both CD4(+) and CD8(+) T cells are required for the induction of colitis accompanied by activation of both T-cell lineages and DCs, increased expression of mucosal IFN gamma, TNF alpha, IL6, IL1 beta, and IL12, and decreased frequencies of CD4(+)FoxP3(+) regulatory T cells. Development of colitis required CD40L expression in CD4(+) T cells, and the disease was partially ameliorated by IFN gamma neutralization. Conclusions: This novel model provides an important tool for studying IBD pathogenesis, in particular the complex interactions among innate and adaptive immune cells in a controlled fashion, and represents a valuable tool for preclinical evaluation of novel therapeutics.