The human adaptive immune system is made up of T and B lymphocytes working together to regulate immune responses to harmful pathogens. T lymphocytes develop in the thymus and mediate cellular immunity. T lymphocytes mature before being sent out to the periphery, where they may eventually encounter their target antigen and differentiate more fully into effector T cells, such as CD4+ helper and CD8+ cytotoxic T cells.
Naïve CD4+ T cells are one of many types of T lymphocytes in the human body. These cells are fully mature, but they have not been activated through an encounter with their target antigen. Once activated in the periphery, naive CD4+ T cells differentiate into subsets of helper T cells that produce different combinations of cytokines and other factors. Each of these T helper subsets has a specific role in defending the body from different pathogens, primarily by influencing other immune cells through cytokines they produce.
During development in the thymus, naive CD4+ and CD8+ T cells express antigen-specific T cell receptors. Once mature, they egress into the periphery, where they continually scan for their target antigen. While still naive, human T cells express the surface markers CD45RA, CD62L, CD127, CD132, and CCR7. At this stage, they are unable to produce pro-inflammatory cytokines and do not express the common activation markers that would be present on fully activated effector T cells. The ratio of naive T cells to antigen-experienced T cells shifts over time, with younger individuals having more naive T cells. As they age and are exposed to more and more pathogens and other antigens over time, the number of antigen-experienced memory T cells increases.
The activation of naïve CD4+ T cells is facilitated by antigen-presenting cells (APCs). Antigen is presented by these cells as part of a complex with major histocompatibility complex (MHC) II molecules. The differentiation of naive T cells into specific lineages depends on a variety of factors, including the cytokines present in the surrounding microenvironment, the costimulatory molecules present on the APC, and the amount of antigen presented by the APCs. The various subsets of CD4+ T helper cells each carry out a different function for the immune system. However, when these cells begin to incorrectly recognize host cells as foreign, autoimmunity can develop.
T helper 1 type (Th1) CD4+ T cells are activated by the presence of IL-12 and IFN𝛾, and express the signature transcription factor T-bet. T-bet impairs the expression of genes necessary for differentiation into the other helper subsets. When functioning properly, Th1 cells primarily help to eliminate intracellular pathogens. They do this by secreting cytokines, such as IFN𝛾, that direct macrophages and other mononuclear cells to kill phagocytosed microbes and induce B cells to switch the isotypes of antibody they produce to help enhance the immune system’s suppressive ability. Th1 cells also promote the growth and proliferation of other effector T cells.
The specific cytokines required for T helper type 2 (Th2) CD4+ T cell differentiation is poorly defined but includes IL-4, which can be produced by mast cells and other Th2 cells. Th2 differentiation happens in response to parasitic worm infections or exposure to allergens. The signature transcription factor for Th2 is GATA3, which drives the expression of Th2 specific genes while inhibiting the expression of genes associated with other helper T cell subsets.
Th2 cells are primarily tasked with handling extracellular parasites and are significant contributors to certain allergic diseases. Normal Th2 responses are focused on activating mast cells, eosinophils, and basophils while also promoting tissue repair. Similarly to Th1 cells, improper responses can cause damage to the body. In the case of Th2, this happens in the form of allergies and some types of asthma. In these instances, the Th2 cells respond strongly to antigens when they should not, resulting in a variety of symptoms, such as rashes and airway inflammation.
The third major T helper subset is Th17. This subset is induced by the cytokines such as IL-1, Il-6, and IL-23 that are induced by bacteria and fungi, though a number of other cytokines can influence how this subset behaves in different tissues. The signature transcription factor for Th17 cells is ROR𝛾T. This transcription factor drives the primary cytokine produced by Th17 cells, IL-17, as well as other Th17 associated genes.
Normally, Th17 cells are responsible for the immune response to extracellular fungi and bacteria. They can also play a major role in the development and persistence of some autoimmune diseases. Some of the key effects of IL-17 production include the induction of neutrophil activation and the production of antimicrobial substances by a number of cell types.
Th1, Th2, and Th17 are not the only fully differentiated forms of CD4+ T cells. Others include the following:
Another aspect of T helper subset differentiation is the ability of some CD4+ T cells to switch their T helper type (including the cytokines they produce) to a different T helper subset, a process called plasticity. Th2 and Th17 cells are capable of becoming Th1 cells, and Tregs can become Th17. This allows the immune system to adapt more readily to the current needs, depending on the pathogen or danger signal involved.
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