T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice

Academic Article

Abstract

  • Background & Aims: T helper (Th) 1 and Th2 cell subsets significantly influence the pathological features of inflammation in the gastrointestinal tract in a distinct manner. It is now established that the transfer of CD4+CD45RBHi (RBHi) T cells to either severe combined immunodeficient (SCID) or recombinase activation gene 2-deficient (RAG-/-) mice results in a severe granulomatous hypertrophic colitis mediated by Th1 cells. We have modified this approach to address the role of Th2 cells. Methods: RBHI T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-γ-defective [IFN-γ-/-]) with or without B cells were transferred to T cell receptor (TCR)-β and δ-chain-defective (TCR-/-) or SCID mice. Results: Transfer of Wt RBHi T cells induced wasting disease with severe colitis in the TCR-/- mice. In contrast, IFN-γ-/- RBHi T cells induced severe weight loss and hypoalbuminemia without significant inflammation in the colon. The small intestine of these mice exhibited villus atrophy, a decrease in brush-border enzymes, reduced enterocyte proliferation, and an increased number of goblet cells. The presence of B cells was necessary for these changes, because SCID recipients required cotransfer of B cells, together with IFN-γ-/- RBHi T cells for ileal lesions to develop. Treatment of TCR-/- recipients of IFN-γ-/- RBHi T cells with anti-IL-4 mAb abrogated both the wasting disease and the villus atrophy. Conclusions: Dysregulated Th2 cells cause atrophic changes and goblet cell transformation in the small intestinal epithelium and wasting disease mediated by excess interleukin-4 and B cells.
  • Published In

  • Gastroenterology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Dohi T; Fujihashi K; Koga T; Shirai Y; Kawamura YI; Ejima C; Kato R; Saitoh K; McGhee JR
  • Start Page

  • 672
  • End Page

  • 682
  • Volume

  • 124
  • Issue

  • 3