Main populations of CD4+ effector T cells. When the naïve CD4+ T-helper (Th) cell recognizes a given antigen on the surface of the antigen-presenting cell (APC), the cytokines present in the microenvironment created by the response of the innate immunity play a critical role in dictating the type of effector cell that is subsequently induced. In the presence of IL-2 and IL-4, the naïve Th cell expresses the transcription factor GATA-binding protein-3 (GATA-3) and differentiates into a Th2 cell that, because of its ability to produce IL-4, IL-5, IL-9 and IL-13, is protective against extracellular parasites, but can also be responsible for allergic disorders. In the presence of IL-4 and transforming growth factor beta (TGFβ), the Th2 cell can further differentiate into a Th9 cell, which produces IL-9 and IL-10, whose pathophysiological meaning as well as the possibility that they can also directly originate from the naïve Th cell are still unclear. In the presence of interferons (IFNs) and IL-12, the naïve Th cell expresses T-box expressed in T cells (T-bet) and differentiates into a Th1 cell that, because of the production of IFNγ and lymphotoxin-α (LTα), induces delayed type hypersensitivity (DTH) reactions that are protective against intracellular bacteria, fungi and protozoa, but can also be responsible for autoimmune disorders such as experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveitis (EAU), and peptoglycan-induced arthritis (PIA). In the presence of TNF and IL-6, the naïve Th cells express aryl hydrocarbon receptor (AHR) and differentiate into a Th22 cell that, because of its production of IL-22 and the expression of skin homing chemokine receptors (CCR4 and CCR10), has been hypothesized to be important in skin homeostasis and pathology. In the presence of TGFβ, IL-6 and IL-21 (in mice) or of IL-1 and IL-23 (in humans), the naïve Th cell expresses retinoic acid-related orphan receptor (ROR)γt and differentiates into a Th17 cell that, because of its production of IL-17A, IL-17F, IL-21 and IL-22, is involved in the protection against extracellular bacteria and fungi, but can also be responsible for autoimmune disorders, such as EAE, EAU and collagen-induced arthritis (CIA). The possibility that the Th17 cell is flexible and can shift in the presence of IL-12 to Th1 has been observed in both humans and mice. NK, natural killer cell.