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CD40 ligand is induced in CD4+ Th cells upon TCR stimulation and provides an activating signal to B cells, making CD40 ligand an important molecule for Th cell function. However, the detailed molecular mechanisms, whereby CD40 ligand becomes expressed on the cell surface in T cells remain unclear. Here, we showed that CD40 ligand expression in CD8+ cytotoxic T cells was suppressed by combined epigenetic regulations in the promoter region of the Cd40lg gene, such as the methylation of CpG dinucleotides, histone H3 lysine 9, histone H3 lysine 27, and histone H4 lysine 20. As the transcription factor Th-inducing pox virus and zinc finger/Kruppel-like factor (encoded by the Zbtb7b gene) is critical in Th cell development, we focused on the role of Th-inducing pox virus and zinc finger/Kruppel-like factor in CD40 ligand expression. We found that CD40 ligand expression is moderately induced by retroviral Thpok transduction into CD8+ cytotoxic T cells, which was accompanied by a reduction of histone H3 lysine 9 methylation and histone H3 lysine 27 methylation in the promoter region of the Cd40lg gene. Th-inducing pox virus and zinc finger/Kruppel-like factor directly inhibited the expression of murine CXXC5, a CXXC-type zinc finger protein that induced histone H3 lysine 9 methylation, in part, through an interaction with the histone-lysine N-methyltransferase SUV39H1. In addition, to inhibit CD40 ligand induction in activated CD4+ T cells by the CXXC5 transgene, our findings indicate that CXXC5 was one of the key molecules contributing to repressing CD40 ligand expression in CD8+ cytotoxic T cells.

T lymphocytes, which are central players in orchestrating immune responses, consist of several subtypes with distinct functions. The thymus is an organ where hematopoietic progenitors undergo sequential developmental processes to give rise to this variety of T-cell subsets with diverse antigen specificity. In the periphery, naive T cells further differentiate into effector cells upon encountering antigens. There are several developmental checkpoints during T-cell development, where regulation by a combination of transcription factors imprints specific functional properties on precursors. The transcription factors E2A, GATA-binding protein 3 (Gata3) and RUNT-related transcription factor (Runx) are involved at various stages in the differentiation of double-negative thymocytes and in β-selection, as are transcription factors from the Notch signaling pathway; other transcription factors such as B-cell lymphoma/leukemia 11b (Bcl11b), myeloblastosis viral oncogene homolog (Myb) and inhibitor of DNA binding 3 (Id3) are involved at specific stages. Differentiation of T cells into helper versus cytotoxic cells involves not only antagonistic interplay between Runx and T(h) inducing POZ-Kruppel factor (ThPOK) but also complex interactions between MAZR, Gata3 and Myb in the activation and silencing of genes such as Cd4 and Cd8 as well as the gene that encodes ThPOK itself. A wide range of well-defined transcription factors, including signal transducer and activator of transcriptions (STATs), T-bet, Gata3, nuclear factor of activated T cell (NFAT), adaptor-related protein complex 1 (AP-1) and nuclear factor κB (NF-κB), are known to shape T(h)1/T(h)2 differentiation. Runx and Gata3 also operate in this process, as do c-Maf and recombining binding protein for immunoglobulin Jκ region (RBP-J) and the chromatin-reorganizing protein special AT-rich sequence-binding protein 1 (SATB1). In this review, we briefly discuss how T-cell characteristics are acquired and become divergent from the point of view of transcriptional regulation.