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. 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. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. They play a critical role in orchestrating adaptive immune responses to various microorganisms. 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.
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. IL-12 and IFN γ are two important cytokines for Th1 differentiation. For Th2 differentiation, many cytokines including IL-4, IL-2, IL-7, and thymic stromal lymphopoietin (TSLP) may be involved. 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. 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. Furthermore, cells simultaneously or sequentially exposed to cytokine mixtures whose components that would normally induce different lineage fates may acquire a mixed Th phenotype. Thus, Th cell differentiation involves a complex cytokine network; this is particularly true in vivo.
The coordination of an immune response is critically dependent on the ability of CD4 T cells to perform a unique set of effector functions. 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. 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. These two subsets are restricted in the pattern of cytokines that they can produce. Thus TH1 cells secrete IL-2 and IFN-γ but not IL-4, while TH2 cells produce IL-4 (as well as IL-5, IL-6, IL-10, and IL-13) but not IL-2 or IFN-γ.
Proinflammatory cytokines (e.g., IL-1β, TNF-α) and chemokines (e.g., MCP-1) may directly modulate neuronal activity in various classes of neurons in the peripheral and central nervous system. In the peripheral nervous system, abnormal spontaneous activity can be evoked from nociceptive neurons by topical application of TNF-α to the peripheral axons in vivo, or to the somata of the DRG (dorsal root ganglion) neurons in vitro. Large, myelinated fast conducting Aβ neurons can also be excited by topical application of TNF-α to the DRG or by an autologous HNP extract. TNF-α can enhance the sensitivity of sensory neurons to the excitation produced by capsaicin and this enhancement likely is mediated by the neuronal production of prostaglandins. It was found that TNF-α-induced neuronal excitation is mediated by cAMP-dependent protein kinase (PKA) pathway. The p38 mitogen-activated protein kinase (MAPK) is also involved in TNF-α- induced cutaneous hypersensitivity to mechanical or thermal stimulation. Results obtained from IL-6 knockout mice indicate that IL-6 plays a facilitating role in sympathetic sprouting induced by nerve injury and that its effect on pain behavior is indirectly mediated through sympathetic sprouting in the DRG. Most recently, it is reported that localized inflammation of the DRG up-regulates a number of proinflammatory cytokines including IL-6 and induces abnormal sympathetic sprouting in the absence of peripheral nerve injury. It suggests a possible correlation between inflammatory responses and sympathetic sprouting, which are two well-known mechanisms implicated in various chronic pain states.
These T cell subsets are characterised by their ability to produce certain cytokines. The Thl subset secrete interleukin (IL)-2, gamma-interferon (IFN-y) and lymphotoxin-α (LT-α, and the Th2 subset secrete IL-4, IL-S, IL-9, IL-10 and IL-13. Both subsets secrete IL-3, tumour necrosis factor (TNF-a) and granulocyte/macrophage colony-stimulating factor (GM-CSF). The physiological relevance of the polarisation of T cells has been identified in some diseases, most notably in Leishmania major infection where lethality is associated with a Th2 response. However, not all T cell clones can be classified as Thl or Th2. Studies performed in various laboratories found that many human and mouse clones co-express both Thl and Th2 cytokines. These T cells, which do not produce a discrete cytokine profile, were designated ThO cells. Data also suggest that ThO cells are driven to differentiate to mature Thl or Th2 cells by a number of factors. These factors include the nature of the antigen stimulation, the cytokine milieu and the type of antigen-presenting cells APCs).
Recently a new lineage of CD4+T cells, type 17 helper T (Th17)cells producing the signature cytokines interleukin (IL)-17, IL-21,and IL-22, has been identified.
Homeostasis of T cells can be defined as the ability of the immune system to maintain normal T-cell counts and to restore T-cell numbers following T-cell depletion or expansion. These processes are governed by extrinsic signals, most notably cytokines. Two members of the common g chain family of cytokines, interleukin (IL)-7 and IL-15, are central to homeostatic proliferation and survival of mature CD4+ and CD8+ T cells. Recent evidence suggests that other cytokines, including IL-2, IL-10, IL-12, interferons and TGF- b, as well as the transcription factors T-bet and eomesodermin all play important but different roles at distinct stages of T-cell homeostasis.
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