Regulation and Deregulation of HLA Class II Genes

Abstract

The role of MHC class II molecules in the presentation of antigens to the receptors of T lymphocytes is well documented. A key feature of MHC class II molecules is their extensive allelic polymorphism. The effect of this structural diversity on the presentation of antigens and on restricted recognition by T cells has been extensively studied at the molecular level (Schwartz 1985). Less attention has been given, however, to the effect of quantitative variations in the level of MHC class II gene expression on the activation of T lymphocytes and on the control of the immune response (Matis et al. 1983). Yet it is evident that such quantitative variations must have important functional consequences in both normal and pathological immune responses as well as for the development of tolerance and the generation of the T cell repertoire by selection events occurring in the thymus. The extent of T cell activation has been shown to be dependent on both the concentration of antigen and the cell surface density of MHC class II molecules (Matis et al. 1983). It has also been proposed that positive selection of specific T cell clones in the thymus depends on the density of MHC class II molecules on thymic epithelial cells (Berg et al. 1990). Finally, the aberrant activation of autoreactive T cells observed in autoimmune diseases has been attributed to abnormal expression of class II molecules in specific cell types. From these considerations, it follows that a better understanding of the molecular mechanisms implicated in the fine control of MHC class II gene expression represents an essential objective.

Experimental work from our laboratory was supported by the Swiss National Foundation and the National Multiple Sclerosis Foundation.