Annu Rev Immunol. 2010; 28: 445–489. doi:10.1146/annurev-immunol-030409-101212. # Differentiation of Effector CD4 T Cell Populations Jinfang Zhu, Hidehiro Yamane, and William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892 Jinfang Zhu: jfzhu@niaid.nih.gov; Hidehiro Yamane: hyamane@niaid.nih.gov; William E. Paul: wpaul@niaid.nih.gov ## Abstract CD4 T cells are essential for adaptive immunity against various pathogens and are involved in autoimmunity, asthma, allergies, and tumor immunity. Upon TCR activation in a specific cytokine environment, naive CD4 T cells can differentiate into various T helper (Th) cell lineages, including Th1, Th2, Th17, and iTreg, based on their cytokine production and function. This review summarizes the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the transcription factor networks involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation. ## Keywords CD4 effector T cells; regulatory T cells; T cell differentiation; cytokines; transcription factors; human diseases ## Introduction CD4 T cells are central to immune function, helping B cells produce antibodies, enhancing CD8 T cell responses, regulating macrophage function, and orchestrating immune responses against pathogens. They also regulate/suppress immune responses to control autoimmunity and adjust response magnitude and persistence. CD4 T cells are important for immunologic memory, and their loss makes individuals susceptible to infectious diseases. In HIV, CD4 T cell counts below 200/mm³ increase the risk of opportunistic infections. ## The Th1/Th2 Paradigm CD4 T cells differentiate into Th1 and Th2 cells based on cytokine production and surface molecule expression. Th1 cells produce IFN-γ and lymphotoxin, while Th2 cells produce IL-4, IL-5, and IL-13. Th1 and Th2 cells can be generated in vitro with specific cytokines. Th1 cells require IL-12 and neutralized IL-4, while Th2 cells require IL-2 and IL-4. Th1 and Th2 cells can differentiate from naive CD4 T cells in vitro, and their differentiation is influenced by cytokines. ## Th17 Cells and iTregs Th17 cells, which produce IL-17A, IL-1Annu Rev Immunol. 2010; 28: 445–489. doi:10.1146/annurev-immunol-030409-101212. # Differentiation of Effector CD4 T Cell Populations Jinfang Zhu, Hidehiro Yamane, and William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892 Jinfang Zhu: jfzhu@niaid.nih.gov; Hidehiro Yamane: hyamane@niaid.nih.gov; William E. Paul: wpaul@niaid.nih.gov ## Abstract CD4 T cells are essential for adaptive immunity against various pathogens and are involved in autoimmunity, asthma, allergies, and tumor immunity. Upon TCR activation in a specific cytokine environment, naive CD4 T cells can differentiate into various T helper (Th) cell lineages, including Th1, Th2, Th17, and iTreg, based on their cytokine production and function. This review summarizes the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the transcription factor networks involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation. ## Keywords CD4 effector T cells; regulatory T cells; T cell differentiation; cytokines; transcription factors; human diseases ## Introduction CD4 T cells are central to immune function, helping B cells produce antibodies, enhancing CD8 T cell responses, regulating macrophage function, and orchestrating immune responses against pathogens. They also regulate/suppress immune responses to control autoimmunity and adjust response magnitude and persistence. CD4 T cells are important for immunologic memory, and their loss makes individuals susceptible to infectious diseases. In HIV, CD4 T cell counts below 200/mm³ increase the risk of opportunistic infections. ## The Th1/Th2 Paradigm CD4 T cells differentiate into Th1 and Th2 cells based on cytokine production and surface molecule expression. Th1 cells produce IFN-γ and lymphotoxin, while Th2 cells produce IL-4, IL-5, and IL-13. Th1 and Th2 cells can be generated in vitro with specific cytokines. Th1 cells require IL-12 and neutralized IL-4, while Th2 cells require IL-2 and IL-4. Th1 and Th2 cells can differentiate from naive CD4 T cells in vitro, and their differentiation is influenced by cytokines. ## Th17 Cells and iTregs Th17 cells, which produce IL-17A, IL-1