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J. Exp. Med.,
Volume 187, Number 8, April 20, 1998 1225-1234
Expression by T Cells
By
From the * Division of Immunology, The requirements for interleukin (IL)-12/signal transducer and activator of transcription (Stat)-4
signaling and induction of T cell-specific interferon (IFN)-
Department of
Pathology,
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- and tumor necrosis factor (TNF)-
-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--producing T cells than did diseased mice, suggesting that effects on wasting and colitis resulted from
the attenuation of IFN- 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- expression, IFN-null donors were used for T cell reconstitution in each system. Surprisingly, large
numbers of IFN-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-, 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- gene expression in T lymphocytes.
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