Scientific Report 2005

Immunology

Specificity and Function of Intraepithelial γδT Cells

W.L. Havran, G. Cauvi, M. Haynes, J. Jameson, H.K. Komori, T. Meehan, R. Mills, L. Sharp, D. Witherden

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

Molecules Required for γδ T-Cell Activation

In murine skin, γδ T cells express an invariant γδ T-cell receptor that recognizes an unknown antigen expressed by damaged or malignant neighboring keratinocytes. We propose that in addition to antigen, damaged keratinocytes express molecules that participate in activation of skin γδ T cells by binding to coreceptors or costimulatory molecules on the T-cell surface. Skin γδ cells do not express classical molecules, including CD4, CD8, and CD28, known to affect activation of αβ T cells.

We recently identified several molecules expressed by the skin γδ T cells and keratinocytes that provide important costimulatory signals for activation of γδ
T cells. One such molecule, AMICA/JAML, is uniquely costimulatory for γδ T cells. We also found that the semaphorin Sema4D (CD100) is expressed by skin γδ T cells upon activation and binds to a new member of the plexin superfamily of semaphorin receptors, plexin-B2, expressed on keratinocytes. These novel receptors and receptor-ligand pair most likely play key roles in the interactions between skin γδ T cells and keratinocytes during homeostasis and in skin disorders. We will also examine the role of these molecules in interactions between intestinal intraepithelial γδ T cells and epithelial cells during colitis.

A Role for Intraepithelial γδ T Cells in the Repair of Epithelial Tissue

We recently showed a role for skin γδ T cells in the reepithelialization stage of wound repair. The γδ T cells are activated at wound sites and produce cytokines, including the epithelial growth factors KGF-1 and KGF-2. In the absence of skin γδ T cells, keratinocyte proliferation and tissue reepithelialization after wounding are defective. Recent results indicated that a keratinocyte-responsive γδ T-cell receptor is necessary for activation of the T cells by damaged keratinocytes during wound healing and is also required for the maintenance of T cells in the epidermis. In addition, we found that the skin γδ T cells are necessary for the recruitment of inflammatory cells into the wound site. In a novel mechanism, γδ T cell–produced KGFs stimulate production of hyaluronan by epidermal cells, which then controls migration of macrophages into wounds.

Skin γδ T cells play roles not only in the repair of damaged tissue but also in the normal maintenance of the epidermis. Insulin-like growth factor 1 is required by keratinocytes in the skin for maintenance and during wound healing. We determined that after activation skin γδ T cells produce this growth factor that affects wound healing and apoptosis in the skin.

Together these results indicate a role for skin γδ T cells in multiple aspects of wound repair and for homeostasis of the epithelium. In previous studies, we showed that intestinal intraepithelial γδ T cells play a similar role in responding to tissue damage in a model of colitis. Results in both models support our hypothesis that intraepithelial γδ T cells respond to epithelial damage or disease and play important roles in tissue repair and epithelial homeostasis. Future studies should provide information that will further define the role of γδ T cells in epithelial inflammatory disorders and may be useful in designing or testing new therapies.

Publications

Baccala, R., Witherden, D., Gonzalez-Quintial, R., Dummer, W., Surh, C.D., Havran, W.L., Theofilopoulos, A.N. γδ T cell homeostasis is controlled by IL-7 and IL-15 together with subset-specific factors. J. Immunol. 174:4606, 2005.

Jameson, J.M., Cauvi, G., Sharp, L.L., Witherden, D.A., Havran, W.L. γδ T cell-induced hyaluronan production by epithelial cells regulates inflammation. J. Exp. Med. 201:1269, 2005.

Sharp, L.L., Jameson, J.M., Cauvi, G., Havran, W.L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat. Immunol. 6:73, 2005.

Sharp, L.L., Jameson, J.M., Witherden, D.A., Komori, H.K., Havran, W.L. Dendritic epidermal T-cell activation. Crit. Rev. Immunol. 25:1, 2005.