Thymocyte contact or monoclonal antibody-mediated clustering of α3β1 or α6β4 integrins activate interleukin-6 (IL-6) transcription factors (NF-κB and NF-IL6) and IL-6 production in human thymic epithelial cells

T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin cu (alpha 2, alpha 3, alpha 4, and alpha 6) and beta (beta 1 and beta 4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: alpha 6 beta 4 lined the basal surface of TEC monolayers, whereas alpha 3 beta 1 was found mostly at TEC-TEC contacts; it is noteworthy that both alpha 3 beta 1 and alpha 6 beta 4 became highly enriched also at the boundaries with adherent thymocytes. Functional studies performed with MoAbs anti-beta 1 and -beta 4 integrins showed that beta 1, and, to a much lower extent, beta 4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of alpha 3, alpha 6, beta 1, and beta 4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of NloAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-kappa B nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation. (C) 1998 by The American Society of Hematology.