T Helper Cell Differentiation

T lymphocytes can be functionally divided into CD4+ cells (T helper cells) and CD8+ cells. While TH1 and TH2 cells are the most commonly referenced subset of T helper cells, newer subsets of TH cells including TH17, Treg (regulatory) and TFH (follicular helper) have recently been identified.Antigen-naive T cells are designated THp for precursor of T helper cell. Upon antigen exposure through contact with cells of the innate immune system, a THp cell may undergo differentiation to an uncommitted cell termed TH0. The interaction begins with the presentation of an antigen-MHCII complex on the surface of APC to the TCR/CD3/CD4 complex on naive T cells. This interplay activates the naive T cell, resulting in IL-2R expression, IL-2 secretion, and CD40L upregulation. IL-2 interacts 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 APC. This interaction stimulates the APC to first express CD86, and later CD80. These molecules serve as membrane-bound ligands for T cell membrane CD28. The CD80/86-CD28 interaction is a key connection, because CD28 ligation amplifies IL-2 secretion, induces the appearance of the anti-apoptotic molecule Bcl-XL 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-γ-producing TH1/TH2 precursor. Alternatively, this stage of T cell differentiation has been suggested to represent a mixed population of cells secreting different sets of cytokines. Antigen exposure of a THp cell can result in the development of a TH1 or TH2 cell. The balance between TH1 and TH2 represents a switch which can be used to bias the immune response in one or the other direction. If the cells are actively secreting cytokines (TH1: IFN-γ TH2: IL-4 and IL-5), they can be considered TH1 or TH2 primary effector cells. If they are "resting" but polarized, they could be considered TH1 or TH2 memory cells, which, when reactivated, form TH1 or TH2 memory effector cells.TH1 cells produce proinflammatory cytokines such as IFN-γ, IL-2 and LT-α and are responsible for phagocyte-dependent protective host responses. Effector TH2 cells, in contrast, produce anti-inflammatory cytokines such as IL-4, IL-5, IL-9, IL-10, IL-13, TGF-β, and are responsible for the phagocyte-independent protective host responses. 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. Besides cytokines, TH differentiation is also regulated by transcription factors. An imbalance in the relative abundance of TH1 versus TH2 cells is associated with asthma, atopic diseases, and autoimmune diseases.TH17, Treg and TFH are more recently identified subsets of TH cells. Th17 cells are pro-inflammatory cells characterized by the expression of IL-17A, IL-17F, IL-21, IL-22, IL-23R and the transcription factors ROR-γt and ROR-α. Under normal conditions TH17 cells may play a role in protection from infection at mucosal surfaces. Treg cells are important regulators of potentially detrimental responses against normal self-constituents or commensal microbes and loss of Treg function leads to autoimmune and inflammatory diseases. Tregs are characterized by the expression of CD25 and Foxp3, the latter being a transcription factor required for the maintenance of the Treg lineage. The differentiation pathways of Treg and TH17 cells are closely related as both processes require the presence of TGF-β. TFH cells are a class of effector TH cells that regulate the stepwise development of antigen-specific B cell immunity in vivo. Deployment of CXCR5+ TFH cells to B cell zones of lymphoid tissues and stable interactions with B cells are central to the delivery of antigen-specific TFH function.