CD5 expression is regulated during human T‐cell activation by alternative polyadenylation, PTBP1, and miR‐204

T lymphocytes stimulated through their antigen receptor (TCR) preferentially express mRNA isoforms with shorter 3´ untranslated regions (3´‐UTRs) derived from alternative pre‐mRNA cleavage and polyadenylation (APA). However, the physiological relevance of APA programs remains poorly understood. CD5 is a T‐cell surface glycoprotein that negatively regulates TCR signaling from the onset of T‐cell activation. CD5 plays a pivotal role in mediating outcomes of cell survival or apoptosis, and may prevent both autoimmunity and cancer. In human primary T lymphocytes and Jurkat cells we found three distinct mRNA isoforms encoding CD5, each derived from distinct poly(A) signals (PASs). Upon T‐cell activation, there is an overall increase in CD5 mRNAs with a specific increase in the relative expression of the shorter isoforms. 3´‐UTRs derived from these shorter isoforms confer higher reporter expression in activated T cells relative to the longer isoform. We further show that polypyrimidine tract binding protein (PTB/PTBP1) directly binds to the proximal PAS and PTB siRNA depletion causes a decrease in mRNA derived from this PAS, suggesting an effect on stability or poly(A) site selection to circumvent targeting of the longer CD5 mRNA isoform by miR‐204. These mechanisms fine‐tune CD5 expression levels and thus ultimately T‐cell responses. CD5 is a T‐cell glycoprotein that negatively regulates TCR signaling. Activated T lymphocytes preferentially express mRNA isoforms with shorter 3′ untranslated regions derived from alternative polyadenylation. During T‐cell activation, CD5 is upregulated by a complex mechanism involving alternative polyadenylation, PTBP1 binding to the shorter mRNA and miR‐204 targeting the longer mRNA, resulting in more CD5 expression at the membrane.