T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and wasting disease in T cell-deficient mice.
OBJECTIVE
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(+)CD45RB(Hi) (RB(Hi)) 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
RB(Hi) T cells from wild-type (Wt) mice or mice genetically predisposed to Th2 responses (interferon-gamma-defective [IFN-gamma(-/-)]) with or without B cells were transferred to T cell receptor (TCR)-beta and delta-chain-defective (TCR(-/-)) or SCID mice.


RESULTS
Transfer of Wt RB(Hi) T cells induced wasting disease with severe colitis in the TCR(-/-) mice. In contrast, IFN-gamma(-/-) RB(Hi) 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-gamma(-/-) RB(Hi) T cells for ileal lesions to develop. Treatment of TCR(-/-) recipients of IFN-gamma(-/-) RB(Hi) 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.
Dohi
Taeko
T
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan. dohi@ri.imcj.go.jp
Fujihashi
Kohtaro
K
Koga
Toshiya
T
Shirai
Yuko
Y
Kawamura
Yuki I
YI
Ejima
Chieko
C
Kato
Rie
R
Saitoh
Kiyoshi
K
McGhee
Jerry R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001284:Atrophy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D020397:Goblet Cells / Q000473:pathology*; D007082:Ileum / Q000473:pathology*; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis; D018655:Lymphocyte Count; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D016513:Mice, SCID; D008871:Microvilli / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology*; D018418:Th2 Cells / Q000502:physiology*; D019282:Wasting Syndrome / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control
D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens