Activation of the HLA-DRA gene in primary human T lymphocytes: novel usage of TATA and the X and Y promoter elements

Abstract

Human T lymphocytes express human leukocyte antigen (HLA)-DR-alpha (DRA) upon mitogenic or antigenic stimulation. DR+ T cells are also found in a number of inflammatory and autoimmune diseases and have a proposed role in these diseases. The molecular mechanism of DR regulation in untransformed blood T lymphocytes was studied here by transient transfection of DRA-chloramphenicol acetyltransferase reporter gene constructs. Several novel features of this regulation were observed. During the early stages of T-cell activation by mitogens or antigens, strong promoter induction was exhibited with the proximal 43 bp of the DRA promoter which contains a TATTA motif. Addition of upstream X and Y DNA elements augmented the response. This contrasts with data from transformed cell lines in which the proximal 43 bp produced no detectable promoter function, and the inclusion of X and Y elements is essential for basal level expression. Mutation of the TATTA motif or substitution with a functional but different TATA element produced errant initiation and greatly reduced gene expression. Interestingly, T lymphocytes from a normal donor were DR+ prior to in vitro stimulation, and again, strong promoter activity was observed with 43 bp of proximal sequence. Unexpectedly, the presence of the X and Y elements correlated with a suppression of class II promoter function and surface antigen expression. This study of nontransformed lymphocytes reveals several novel features of DRA gene regulation and underscores the value and necessity of such studies.