CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.
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