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.

Abstract:

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 TGFβ signaling due to dendritic cell-specific knockout of TGFbR2 (TGFβR2ΔDC). Here, we demonstrate that crossing TGFβR2ΔDC 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-/-TGFβR2ΔDC 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 IFNγ, TNFα, IL6, IL1β, 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 IFNγ 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.

journal_name

Inflamm Bowel Dis

authors

Jamwal DR,Marati RV,Harrison CA,Midura-Kiela MT,Figliuolo Paz VR,Besselsen DG,Ghishan FK,Kiela PR

doi

10.1093/ibd/izz191

subject

Has Abstract

pub_date

2020-01-06 00:00:00

pages

229-241

issue

2

eissn

1078-0998

issn

1536-4844

pii

5574760

journal_volume

26

pub_type

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