Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 2 2025 03 04 189 202 Mansoureh Karimi Kakh Department of Immunology, Faculty of Medicine, Kerman University of Medical Science, Kerman, Iran; ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran Morteza Motallebnezhad Student Research Committee, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran Pooria Ghiasi Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran Farzad Nazari ImmunologyToday, Universal Scientific Education and Research Network (USERN), Tehran, Iran 2025 01 16 2025 03 04 CD4+ T helper (Th) cells are part of the adaptive immune system and are responsible for activating other immune cells, such as B cells, CD8+ T cells, macrophages, mast cells, neutrophils, eosinophils, and basophils. Differentiation of CD4+ T cells is influenced by cytokines and stimulation of the T cell receptor by different antigens. The pattern of cytokine secretion can be altered under specific conditions from one cell line to another, indicating that Th cells have plasticity. In fact, active and master regulators collaborate with transcription factors like signal transducers, activator transducers, and activators of transcription (STATs) in developing the differentiation process. The signals provided by cytokines activate specific transcription factors in each cell line. During this process, epigenetic modifications are actively involved. Epigenetics is defined as heritable alterations in the regulation of gene expression without any change in the DNA strand and includes DNA methylation, histone modification, and non-coding RNAs. The plasticity of CD4+ T cells in differentiation to multiple subsets allows Th cells to exhibit the best immune response against the target microorganism. Failure to respond appropriately to multiple types of microorganisms can lead to disease. In this review, we have collected recent advances in understanding the role of epigenetic regulatory mechanisms in the differentiation of Th cells and, thereby, the commitment of CD4+ T cells to a particular lineage to raise an appropriate response against a variety of microorganisms. https://igj.tums.ac.ir/index.php/igj/article/view/169 https://igj.tums.ac.ir/index.php/igj/article/download/169/176