Abstract
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naïve versus antigen-experienced CD8+ T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. Cancer Immunol Res; 6(1); 69-78. ©2017 AACR.
Highlights
Costimulation dictates the outcome of antigen recognition by T cells
Our initial hypothesis was that CD137 signaling in primed T lymphocytes would result in chromatin remodeling through sequence-specific genomic DNA methylation
In order to assess nuclear gene DNA methylation in a genome-wide fashion, the 450K DNA-methylation array was used in a series of CD8þ T cells from three independent individuals costimulated by urelumab or by 6B4 acting on CD8þ T cells from an additional unrelated donor
Summary
Costimulation dictates the outcome of antigen recognition by T cells. Gene expression, and metabolism take place if costimulation is provided [1] but, in addition, subtle long-term changes occur that leave T cells poised to more robustly respond if challenged at a later time point with antigen [2]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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