RECIPROCAL CYTOKINE-MEDIATED CELLULAR INTERACTIONS IN MOUSE EPIDERMIS - PROMOTION OF GAMMA-DELTA T-CELL GROWTH BY IL-7 AND TNF-ALPHA AND INHIBITION OF KERATINOCYTE GROWTH BY GAMMA-DELTA IFN

A unique subset of gammadelta T cells, termed dendritic epidermal T cells (DETC), resides in symbiosis with keratinocytes in mouse epidermis. We have shown previously that interleukin 7 (IL-7) which is produced by keratinocytes, promotes growth and prevents apoptosis in DETC. To extend this observation, we examined 12 cytokines, each of which is expressed by epidermal cells at mRNA and/or protein levels, for their capacities to modulate the growth of DETC. Cytokines examined included IL-1alpha, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, tumor necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma), granulocyte/macrophage-colony stimulating factor (GM-CSF), and macrophage inflammatory protein-1alpha (MIP-1alpha). When tested individually, IL-2 and IL-7 promoted maximal growth of the long-term cultured DETC line 7-17. When tested in combinations, synergistic growth-promoting effects were seen with IL-2 and IL-4 or IL-7, and with IL-7 and IL-4 or TNFalpha. Dose-response experiments demonstrated that TNFalpha, which is produced by keratinocytes, enhances IL-7-induced DETC proliferation, but inhibits IL-2-induced proliferation. The mouse keratinocyte-derived cell line Pam 212 was used to test these cytokines for their capacities to regulate keratinocyte growth. Only gammaIFN, which is produced by DETC, inhibited proliferation in a dose-dependent fashion. These results illustrate three reciprocal pathways by which epidermal cytokines regulate the growth of epidermal cells: 1) a paracrine mechanism by which keratinocyte-derived cytokines (e.g., IL-7 and TNFalpha) promote the growth of DETC, 2) an autocrine mechanism by which DETC-derived cytokines (e.g., IL-2 and IL-4) support their own growth, and 3) a reciprocal pathway in which a cytokine produced by resident epidermal leukocytes (e.g., gammaIFN) modulates the growth of keratinocytes.