THC Differentiation Pathway

The abbreviations TH1 (T-helper Cell type 1) and TH2 (T-Helper Cell type 2) refer to CD4+ alpha-beta TCR T-Cell subsets that provide help to cells of both the innate and adaptive immune systems. TH3 cells share certain characteristics common to both TH1 and TH2 cells; however, their apparently unique regulatory and functional roles have defined them as a novel sub-type. Antigen-naive T-cells are designated THp for precursor of T-helper cell. THp cells have been traditionally described as exclusively IL-2 producers, but they can be highly diverse in cytokine production upon initial activation (i.e., IL-2, IL-4, TNF-beta, IL-13, IFN-gamma). Upon antigen exposure through contact with cells of the innate immune system, a THp cell may undergo differentiation to an uncommitted cell termed TH0 [2]. This interaction begins with the presentation of an antigen-MHC class II complex on the surface of an APC (antigen-presenting cell) to the TCR/CD3/CD4 complex on naive T lymphocytes. This interplay activates the naive T cell, resulting in IL-2 receptor expression, IL-2 secretion, and CD40L upregulation. IL-2interacts with IL-2R in an autocrine manner, while the appearance of CD40L allows the T cell to bind constitutively expressed CD40 on the surface of the APC. This interaction stimulates the APC to first express CD86/B7-2, and later CD80/B7-1. These molecules serve as membrane-bound ligands for T cell membrane CD28. The B7-CD28 interaction is a key connection, because CD28 ligation amplifies IL-2 secretion, induces the appearance of the anti-apoptotic molecule BCL-XL (promoting survival), and may contribute to future cytokine secretion. While the exact nature of the TH0 cell produced from THp cells is unclear, it has been described as an IL-4 and IFN-gamma producing TH1/TH2 precursor. Alternatively, this stage of T cell differentiation has been suggested to represent a mixture or population of cells secreting multiple varieties of cytokines. Antigen exposure to a THp cell results in the final creation of either a TH1 or TH2 cell, either effector or memory cells. The balance between TH1 and TH2 represents a sort of switch, which can be used to bias immune response in one or other direction. The commitment of TH0 cells to become TH1 or TH2 is influenced by cytokines secreted by the 2 subtypes themselves and by macrophages, NK cells and mast cells. If the cells are actively secreting cytokines (e.g., TH1: IFN-gamma; TH2:IL-4 and IL-5), They can be considered TH1 or TH2 primary effector cells. If they are "resting" but polarized (i.e., committed to a TH type), they could be considered TH1 or TH2 memory cells, which, when reactivated, form TH1 or TH2 memory effector cells [3].

TH1 cells produce pro-inflammatory cytokines such as IFN-Gamma (Interferon-Gamma), IL-2, and LT-Alpha (Lymphotoxin-Alpha) and are responsible for phagocyte-dependent protective host responses. Effector TH2 cells, in contrast, produce anti-inflammatory cytokines like IL-4 (Interleukin-4), IL-5, IL-9, IL-10, IL-13, TGF-Beta and so forth, and have been considered responsible for the phagocyte-independent protective host responses [4]. In humans, both TH1 and TH2 subsets secrete IL-10. Chemokine receptors CXCR-3 and CCR-5 are characteristic of TH1 cells, while CXCR-4, CCR-3, CCR-4, CCR-7, and CCR-8 are associated with TH2 cells. CD30, a member of the TNF superfamily, is associated with TH2 cells. Interestingly, the cytokines produced by each TH subset tend to both stimulate production of that TH subset, and inhibit development of the other TH subset. That is, IFN-Gamma produced by TH1 cells has the dual effect of both stimulating TH1 development and inhibiting TH2 development. TH2-secreted IL-10 has the opposite effect. Besides cytokines, TH differentiation is also regulated by certain transcription factors. TH1 differentiation is regulated by transcription factors such as T-bet, Stat1, and Stat4, where as the transcription factors Stat6, GATA-3, c-Maf, NFATs, promote TH2 differentiation. Another TH cell type with a unique cytokine secretion pattern is the TH3 cell, which appears to be a CD4+ immune regulatory T cell that secretes TGF-beta. An imbalance in the relative abundance of TH1 versus TH2 cells has been associated with asthma, atopic diseases, and autoimmune diseases. Endotoxin, a bacterial compound, is a potent stimulator of TH1 cells. Therefore, TH1 cells secrete cytokines that predominantly activate intracellular defenses against bacteria. On the other hand, a number of intractable viruses and parasites, such as HIV, hepatitis B and C, and malaria induce cellular responses that favor the TH2 sub-type allowing virally infected cells to remain undetected by the immune system. Activated TH2 cells, also usually associated with atopic diseases, secrete cytokines that activate extracellular defense mechanisms [5,6].