Abnormal regulation of retinoic acid receptor beta2 expression and compromised allograft rejection in transgenic mice expressing antisense sequences to retinoic acid receptor beta1 and beta3.

Abstract

Transgenic mice carrying antisense sequences common to the retinoic acid receptors (RAR) beta1 and beta3 were produced to examine roles of RARbeta1 and beta3 in the immune system. There were no significant changes of endogenous RARbeta1/beta3 expression at the mRNA level in T cells, B cells, and macrophages of the transgenic mice (AS-RARbeta1/beta3 mice). However, there was a decrease of RARbeta1/beta3 protein in the T cells, as expected. Interestingly, a drastic up-regulation (7-10 fold) of RARbeta2 messages and a significant decrease of RARbeta4 messages in AS-RARbeta1/beta3 macrophages were observed compared with that of nontransgenic macrophages. RARbeta2 protein in the transgenic macrophages was also up-regulated. This suggests that there is a dual feedback control for the RARbeta expression. A repressed RARbeta1 and beta3 expression, presumably at the protein level, likely leads to a compensatory up-regulation of RARbeta2 and repression of RARbeta4, which is less active than RARbeta2. The AS-RARbeta1/beta3 mice had no gross abnormality. However, they had compromised rejection response to cardiac allografts. The alloantigen-specific T cell cytotoxicity was reduced, and the macrophage population in the spleen was decreased in these mice. These defects likely contribute to the slower rejection response in the AS-RARbeta1/beta3 mice, the existence of other defects not being excluded. Our study has suggested that RARbeta1 and RARbeta3 are necessary to optimize immune responses.