CD8+ cytotoxic T cells induce relapsing colitis in normal mice.
OBJECTIVE
Most mouse models of IBD have emphasized an effector role of type-1 CD4+ T cells in colitis. The aim of this study was to develop a model of antigen-specific relapsing colitis to investigate the relative contribution of CD4+ and CD8+ effectors.


METHODS
Balb/C mice were sensitized and challenged with a suboptimal dose of 2.4 dinitrobenzene sulfonic acid to generate a colonic delayed-type hypersensitivity response. The respective role of CD4+ and CD8+ T cells in the initiation of colitis was analyzed by in vivo monoclonal antibody depletion and cell-transfer experiments. Dynamic and function of the colitogenic effectors were studied by immunohistochemistry, fluorescence-activated cell sorter analysis, enzyme-linked immunospot assay, quantitative polymerase chain reaction, and in vivo CTL assays.


RESULTS
Relapsing colitis rapidly occurred only after challenge of previously sensitized mice. Interferon-gamma-producing cytotoxic CD8+ T cells (Tc1) specific for hapten-modified self-proteins were generated in colon-draining lymph nodes on day 5 after sensitization, before the onset of disease. These CD8+ T cells were rapidly recruited upon challenge into colon lamina propria as granzyme B-expressing effectors exerting ex vivo cytotoxicity against syngeneic hapten-modified colonic epithelial cells. Colitis was prevented by in vivo antibody depletion of CD8+, but not of CD4+, T cells and could be induced in naive recipients within 48 hours after transfer of CD8+, but not CD4+, T cells purified from sensitized mice.


CONCLUSIONS
Our data show that antigen-specific CD8+ T cells can induce relapsing colitis in normal mice and suggest that the cytolytic function of CD8 Tc1 against epithelial cells may initiate the intestinal inflammatory process.
Nancey
Stéphane
S
INSERM U 404 Immunité et Vaccination, CERVI, IFR 128 Biosciences Lyon-Gerland, Lyon, F-69007, France.
Holvöet
Sébastien
S
Graber
Ivan
I
Joubert
Grégoire
G
Philippe
David
D
Martin
Stefan
S
Nicolas
Jean-François
JF
Desreumaux
Pierre
P
Flourié
Bernard
B
Kaiserlian
Dominique
D
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA