These two subsets are restricted in the pattern of cytokines that they can produce. Although most antigen-specific CD4 T cells have the potential to secrete all of these cytokines, CD4 T cells exposed to specific microenvironments can differentiate into two distinct subsets, termed T helper 1 (TH1) and T helper 2 (TH2) cells. Crucial among these effector functions is the capacity of CD4 T cells to secrete a distinctive array of cytokines including IL-2, IL-4, and IFN-γ. The coordination of an immune response is critically dependent on the ability of CD4 T cells to perform a unique set of effector functions. Thus, Th cell differentiation involves a complex cytokine network this is particularly true in vivo. Furthermore, cells simultaneously or sequentially exposed to cytokine mixtures whose components that would normally induce different lineage fates may acquire a mixed Th phenotype. In gen-eral, more than one cytokine is required for differentiation to any particular phenotype and cytokines that promote differen-tiation to one lineage may suppress adoption of other lineage fates. While transforming growth factor-β (TGFβ) induces Th17 differentiation in the presence of IL-6, it also promotes iTreg cell differentiation when IL-2 but not IL-6 is available. For Th2 differentiation, many cytokines including IL-4, IL-2, IL-7, and thymic stromal lymphopoietin (TSLP) may be involved. IL-12 and IFN γ are two important cytokines for Th1 differentiation. The major determinant for Th cell differentiation is the cytokine milieu at the time of antigen encounter, although the nature of cognate antigen and its affinity to the TCR as well as the available costimulants, many of which regulate initial cytokine production, can influence Th cell fate. They can be distinguished by their unique cytokine production profiles and their functions:Th1 cells predominantly produce interferon-γ (IFNγ) and are important for protective immune responses to intracellular viral and bacterial infection Th2 cells, by producing interleukin-4 (IL-4), IL-5, IL-9, IL-13, and IL-25, are critical for expelling extracellular parasites such as helminths Th17 cells are responsible for controlling extracellular bacteria and fungi through their production of IL-17a, IL-17f, and IL-22 inducible T-regulatory (iTreg) cells, together with naturally occurring T-regulatory (nTreg) cells, are important in maintaining immune tolerance, as well as in homeostasis, activation and function. They play a critical role in orchestrating adaptive immune responses to various microorganisms. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. Our understanding of the importance of the distinct differentiated forms of CD4 T cells and of the mechanisms through which they achieve their differentiated state has greatly expanded over the past 2 decades. In 1986, Mosmann and Coffman identified 2 subsets of activated CD4 T cells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and their functions.
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