The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1225/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1225-1234

Articles

T Cell–mediated Pathology in Two Models of Experimental Colitis Depends Predominantly on the Interleukin 12/Signal Transducer and Activator of Transcription (Stat)-4 Pathway, but Is Not Conditional on Interferon {gamma} Expression by T Cells

Stephen J. Simpson*, Samir Shah*, Martina Comiskey*, Ype P. de Jong*, Baoping Wang*, Emiko Mizoguchi{ddagger}, Atul K. Bhan{ddagger}, and Cox Terhorst*

From the * Division of Immunology, Beth Israel Deaconess Medical Center and the {ddagger} Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115

The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4 signaling and induction of T cell–specific interferon (IFN)-{gamma} expression in the development of T helper cell (Th)1–type pathology were examined in two different models of experimental colitis. In each model, abnormal reconstitution of the T cell compartment in immunodeficient mice by adoptive cell transfer leads to a wasting syndrome and inflammation of the colon, induced by IFN-{gamma} and tumor necrosis factor (TNF)-{alpha}–producing T cells. We show here that treatment with anti–IL-12 antibodies in one of the models, or reconstitution with T cells from Stat-4–deficient (Stat-4null) mice in both models resulted in a milder disease in the majority of recipient animals, compared with those that were left untreated or that had been reconstituted with wt cells. Protected mice in each group also harbored lower frequencies of IFN-{gamma}–producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from the attenuation of IFN-{gamma} expression by T cells. To test whether the development of pathogenic T cells in the two colitis models was directly dependent on T cell–specific IFN-{gamma} expression, IFN-{gamma}null donors were used for T cell reconstitution in each system. Surprisingly, large numbers of IFN-{gamma}null–reconstituted mice developed wasting and colitis, which in many cases was of comparable severity to that seen in animals reconstituted with wt cells. Furthermore, T cells from these animals expressed TNF-{alpha}, demonstrating that they had retained the ability to produce another proinflammatory cytokine. Taken together, these results demonstrate that in some forms of chronic experimental colitis the development of pathogenic T cells is influenced predominantly, though not exclusively, by IL-12 via the actions of Stat-4 proteins. Furthermore, our data suggest that in the models of colitis studied here the effects of IL-12/Stat-4 or other Th1 promoting pathways are not limited to the induction of IFN-{gamma} gene expression in T lymphocytes.

Address correspondence to Cox Terhorst, Division of Immunology, Beth Israel Hospital, 330 Brookline Ave., Harvard Medical School, Boston, MA 02115. Phone: 617-667-7147; Fax: 617-667-7140.

1Abbreviations used in this paper: BM-> Tg{varepsilon}26, (C57BL/6 x CBA/J)F1; BMC; bone marrow cells; IBD; inflammatory bowel disease; Stat, signal transducer and activator of transcription; TGF, transforming growth factor.

Stephen J. Simpson's present address is Education and Research Centre, St. Vincent's Hospital, Dublin 4, Ireland.

Simpson and Shah contributed equally to this work.

2 Mackay, F., J. Browning, P. Lawton, S. Shah, M. Comiskey, A.K. Bhan, E. Mizoguchi, C. Terhorst, and S. Simpson, manuscript submitted for publication.


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