News and Publications

Development and Function of Intraepithelial T Cells

W.L. Havran, K. Albers, N. Chen, Y. Chen, S. Rieder, D. Witherden, T. Wu

This laboratory has a long-term interest in interactions between intraepithelial T cells and neighboring epithelial cells. We have focused our studies on interactions in the thymus, skin, and intestine. We are investigating the development, specificity, and function of these T cells. Our results have defined unique properties of these cells and support a specialized role for epithelial T cells in immune surveillance, wound repair, inflammation, and protection from malignant tumors.

CD81 IN T-CELL DEVELOPMENT AND FUNCTION

CD81 is a member of the 4 transmembrane spanning family of membrane proteins. It is broadly expressed and can associate with other cell-surface molecules in a cell type--specific manner. No clear function has been defined for CD81 or other members of this family. We showed that interactions between CD81 on thymic epithelial cells and immature thymocytes occur during a discrete stage of development. In addition, CD81 is expressed by epithelial cells in the skin and intestine and plays a role in the activation of intraepithelial T cells. CD81 is also expressed by mature ß T cells in lymphoid organs and provides costimulatory activity when coligated with the antigen receptor. These results indicate that CD81 can play diverse roles in T-cell development and function by tissue- and cell type--specific associations. Future studies will focus on unraveling some of the complexities of this molecule.

ANTIGENS FOR T CELLS

Close physical interactions between T cells and neighboring epithelial cells suggested the possibility of functional interactions between these 2 populations. We showed that T cells in the skin monitor neighboring keratinocytes for signs of damage or disease. If a problem is detected, the T cells secrete growth factors and chemokines that contribute to tissue repair and direct recruitment of other cell types to sites of trauma. We isolated the antigen for the skin T cells from damaged keratinocytes. Most ß T cells recognize peptide antigens derived from foreign proteins and presented by self-MHC molecules. In contrast, the antigen is nonpeptidic and does not require MHC molecules for presentation. Experiments are in progress to further define this novel antigen. The recognition of unique antigens and the ability to perform specialized functions support a novel immunologic role for intraepithelial T cells.

A ROLE FOR INTRAEPITHELIAL T CELLS IN EPITHELIAL INFLAMMATION

Our previous studies indicated that intraepithelial T cells in the skin and intestine inducibly produce the epithelial growth factor KGF. In addition, these cells produce a panel of cytokines and chemokines that may recruit inflammatory cells and modulate the growth and function of neighboring cells. We proposed that intraepithelial T cells may play an important role in epithelial homeostasis in normal and disease conditions.

To test this hypothesis, in collaboration with R. Boismenu, Department of Immunology, we analyzed the role of intestinal T cells in a murine model of colitis. In this model system, focal areas of inflammation appear in the large intestine after animals are fed dextran sodium sulfate. We found increased numbers of T cells at these sites and have evidence that the cells are activated and are producing cytokines and chemokines locally. In particular, using in situ hybridization, we showed that the T cells in the animals with colitis produce higher levels of KGF than do T cells in control animals.

In collaboration with the Strohm Inflammatory Bowel Disease Center at Scripps Clinic, we analyzed tissue and blood samples from patients with ulcerative colitis or Crohn's disease. We found that these patients have greater numbers of T cells both in blood and at sites of active disease than healthy subjects or patients with cancer do. In addition, we found that levels of KGF in the patients with ulcerative colitis or Crohn's disease were higher at sites of inflammation than at uninvolved sites. These results validate the mouse model of colitis and support our hypothesis. Future studies should provide information to further define the role of T cells in epithelial inflammatory disorders and may be useful in designing therapies.

PUBLICATIONS

Boismenu, R., Chen, Y., Havran, W.L. The role of intraepithelial T cells: A gut feeling. Res. Immunol., in press.

Boismenu, R., Havran, W.L. T cells in host defense and epithelial cell biology. Clin. Immunol. Immunopathol. 86:121, 1998.

Domanico, S.Z., Pelletier, A.J., Havran, W.L., Quaranta, V. Integrin _6Aß₁ induces CD81-dependent cell motility without engaging the extracellular matrix migration substrate. Mol. Biol. Cell 8:2253, 1997.

Havran, W.L., Chen, Y., Boismenu, R. Innate functions of epithelial T cells. In: Mechanisms of Lymphocyte Activation and Immune Regulation. VII: Molecular Determinants of Microbial Immunity. Gupta, S., Sher, A., Ahmed, R. (Eds.). Plenum, New York, in press.

Punt, J.A., Havran, W.L., Abe, R., Sarin, A., Singer, A. T cell receptor (TCR)-induced death of immature CD4⁺CD8⁺ thymocytes by two distinct mechanisms differing in their requirements for CD28 costimulation: Implications for negative selection in the thymus. J. Exp. Med. 186:1911, 1997.