Overexpression of LFA-1 and ICAM-1 in Down syndrome thymus. Implications for abnormal thymocyte maturation.

Abstract

The interaction between lymphocyte function-associated antigen 1 (LFA-1) on thymocytes and intercellular adhesion molecule 1 (ICAM-1) on the thymic stroma plays an important role in thymocyte maturation. Consequently, we examined the constitutive expression of LFA-1 and ICAM-1 in postnatal human thymus from children with Down syndrome (trisomy 21, DS) and age-matched control children. We studied DS thymuses because this aneuploid condition is associated with abnormal thymic anatomy and patterns of thymocyte maturation and the affected individuals have a greatly increased incidence of infection. In addition, the beta-chain for LFA-1 is encoded on human chromosome 21, suggesting that trisomy 21 thymocytes may overexpress this adhesion molecule. Using immunofluorescence and flow cytometry, LFA-1 beta expression was evaluated in eleven pairs of DS and age-matched control thymocytes. The mean channel of fluorescence for LFA-1 beta expression was significantly higher in DS thymocytes than in the controls (p < or = 0.01). Six of the 11 pairs were examined for LFA-1 alpha chain expression. DS thymocytes also showed significantly higher levels of LFA-1 alpha expression (p < or = 0.05), which is consistent with findings that surface expression of the LFA-1 alpha chain is dependent on beta-chain expression. Using immunohistochemical analysis and quantitative video imaging, we examined the level of ICAM-1 expression on frozen sections from four pairs of DS and control thymuses, and found nearly twofold higher levels of ICAM-1 expression in the DS thymuses (p < or = 0.05). DS thymuses also showed a diffuse pattern of ICAM-1 expression with elevated staining in both cortex and medulla and poor demarcation of staining at the cortico-medullary junctions. Given our recent observation that DS thymuses overexpress mRNA for IFN-gamma and TNF, and the fact that both of these cytokines induce ICAM-1 expression on cultured human thymic epithelial cells, we propose that increased levels of IFN-gamma and TNF contribute to the enhanced expression of ICAM-1 in DS thymuses. Our findings support a role for cytokines in the regulation of adhesion molecule expression in the thymus and suggest that the increased expression and abnormal distribution of adhesion molecules in DS thymuses alters the interaction between developing thymocytes and the thymic stroma and results in the abnormal thymocyte maturation observed in DS.