OVEREXPRESSION OF LFA-1 AND ICAM-1 IN DOWN-SYNDROME THYMUS - IMPLICATIONS FOR ABNORMAL THYMOCYTE MATURATION

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. Conseq uently, 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 t his 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 2 1 thymocytes may overexpress this adhesion molecule. Using immunofluor escence and flow cytometry, LFA-1beta expression was evaluated in elev en pairs of DS and age-matched control thymocytes. The mean channel of fluorescence for LFA-1beta expression was significantly higher in DS thymocytes than in the controls (p less-than-or-equal-to 0.01). Six of the 11 pairs were examined for LFA-1alpha chain expression. DS thymoc ytes also showed significantly higher levels of LFA-1alpha expression (p less-than-or-equal-to 0.05), which is consistent-with findings that surface expression of the LFA-1alpha chain is dependent on beta-chain expression. Using immunohistochemical analysis and quantitative video imaging, we examined the level of ICAM-1 expression on frozen section s from four pairs of DS and control thymuses, and found nearly twofold higher levels of ICAM-1 expression in the DS thymuses (p less-than-or -equal-to 0.05). DS thymuses also showed a diffuse pattern of ICAM-1 e xpression with elevated staining in both cortex and medulla and poor d emarcation of staining at the cortico-medullary junctions. Given our r ecent observation that DS thymuses overexpress mRNA for IFN-gamma and TNF, and the fact that both of these cytokines induce ICAM-1 expressio n 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 th e regulation of adhesion molecule expression in the thymus and suggest that the increased expression and abnormal distribution of adhesion m olecules in DS thymuses alters the interaction between developing thym ocytes and the thymic stroma and results in the abnormal thymocyte mat uration observed in DS.