01.07 Control of chronic inflammation by t-bet expressed in th cells

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Abstract

Background

The transcription factor ‘T-box expressed in T cells’ (T-bet) is highly expressed by Th cells isolated from the inflamed tissue in many chronic inflammatory diseases. Here we have analysed in detail the contribution of T-bet in shaping the inflammation in the T-cell transfer induced colitis model as a prototypic model for T cell mediated chronic, progressive inflammation.

Methods

To induce colitis Tbx21-deficient Th cells were adoptively transferred into Rag-deficient mice. Intestinal inflammation was characterised by quantitative and qualitative analysis of lamina propria-infiltrating cells, Th cell phenotyping and histology.

Results

Here we show that the requirement for T-bet expression by Th cells for the manifestation of clinical symptoms of T cell-induced colitis is absolutely dependent on the composition of the intestinal microbiota. When colitis develops, T-bet exerts several non-redundant functions in shaping the inflammation. T-bet expressed by Th cells promotes the survival and positioning of the Th cells in the colon and their repertoire of chemokine and chemokine receptor expression, the recruitment of myeloid cells to the inflamed colon, and the differentiation of macrophages/monocytes. Remarkably, in T cell-induced colitis, T-bet-deficient Th cells differentiate into Th1/17 cells, able to express IFN-γ and IL-17 upon restimulation. Th cell-derived IFN-γ or IL-17, however, are not required to induce colitis.

Conclusions

We demonstrate that while T-bet shapes the type of the intestinal inflammatory reaction, it is not an essential pre-requisites for T cell-induced colitis. Our data show that the key cytokines IFN-γ and IL-17 play a subordinate role in colitis induction and suggest that the type of inflammation is determined by the chemokine expression profile of the Th cells. In addition, whether Th cells are pathogenic is largely determined by the composition of the intestinal microbiota. Thus, our data shed light on the heterogeneity of inflammatory bowel diseases and their variable response to therapy depending on the microbiota composition and the Th cells involved.

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