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

Deepa Rana Jamwal, Raji V. Marati, Christy A. Harrison, Monica T. Midura-Kiela, Vanessa R. Figliuolo Paz, David G. Besselsen, Fayez K. Ghishan, Pawel R. Kiela

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)229-241
Number of pages13
JournalInflammatory bowel diseases
Volume26
Issue number2
DOIs
StatePublished - Jan 6 2020

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Colitis
Inflammatory Bowel Diseases
Cell Communication
Dendritic Cells
T-Lymphocytes
Cell Lineage
CD40 Ligand
Adoptive Transfer
Regulatory T-Lymphocytes
Interleukin-12
Disease Progression
Interleukin-6

Keywords

  • adoptive transfer
  • autoimmunity
  • CD40L
  • dendritic cells
  • IFNγ
  • inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

Cite this

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. / Jamwal, Deepa Rana; Marati, Raji V.; Harrison, Christy A.; Midura-Kiela, Monica T.; Figliuolo Paz, Vanessa R.; Besselsen, David G.; Ghishan, Fayez K.; Kiela, Pawel R.

In: Inflammatory bowel diseases, Vol. 26, No. 2, 06.01.2020, p. 229-241.

Research output: Contribution to journalArticle

Jamwal, Deepa Rana ; Marati, Raji V. ; Harrison, Christy A. ; Midura-Kiela, Monica T. ; Figliuolo Paz, Vanessa R. ; Besselsen, David G. ; Ghishan, Fayez K. ; Kiela, Pawel R. / 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. In: Inflammatory bowel diseases. 2020 ; Vol. 26, No. 2. pp. 229-241.
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AU - Jamwal, Deepa Rana

AU - Marati, Raji V.

AU - Harrison, Christy A.

AU - Midura-Kiela, Monica T.

AU - Figliuolo Paz, Vanessa R.

AU - Besselsen, David G.

AU - Ghishan, Fayez K.

AU - Kiela, Pawel R.

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AB - 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.

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