Modulation of integrin‐mediated intercellular adhesion during the interaction of thymocytes with stromal cells expressing VLA‐4 and LFA‐1 ligands

Mature peripheral T cells closely regulate their intercellular interactions by modulating integrin adhesion functions. The ability of members of the integrin family to mediate intercellular adhesion is dependent on signals from within the cells (inside‐out signaling) that increase the avidity of integrins for their ligands. These changes in avidity are independent of the quantitative changes on the number of receptors, and there is evidence to suggest that phosphorylation events play a predominant role in the regulation of the avidity state of the integrins. Whether such regulatory mechanisms are operative during T cell development had hitherto been an opened question. In the present work, we have used an in vitro adhesion assay between thymocytes and target cells expressing VLA‐4 and LFA‐1 counter ligands to determine how thymocytes can discriminate between integrin‐specific signals during T cell development. Our findings are that VLA‐4, but not LFA‐1, is constitutively expressed in its high‐avidity state during the early stages of T cell development, and that the high‐avidity state of thymocytes for VCAM‐1‐expressing cells is closely regulated by signaling through protein kinase C and protein tyrosine kinase pathways. At later stages of development, mature thymocytes prior to leaving the thymus turn off both VLA‐4 and LFA‐1 adhesion functions. Our results show that the low‐affinity state of integrins on peripheral mature T cells is established before mature thymocytes leave the thymus. Only when mature T cells recognize antigenic peptides in the context of major histocompatibility complex in the periphery will they turn on the adhesion function of VLA‐4 and/or LFA‐1 integrins.