Preventing the body from autoimmune disease and chronic disease as well as from a too weak immune response is a crucial function of the immune regulation. Different mechanisms of immune regulation are known. One of the most important part of the peripheral immune regulation, the so-called peripheral tolerance, are the regulatory T cells, also known as Treg. On the one hand Treg has a important role in preventing autoimmune disease like type 1 diabetes and others. On the other hand they obstruct the response against tumours and certain pathogens.
Regulatory T cells are characterized by FOXP3 activity. FOXP3 is required for the maintenance, function and development of regulatory T cells. FOXP3 is not the only factor for these scopes but the absence of FOXP3 leads to severe autoimmune disease. It is also known that thymus-derived Treg naturally express CD25 and CD4. This is the main group of regulatory T cells.
Suppression mechanisms can be divided in four parts and is possible through inhibitory cytokines, cytolysis, metabolic disruption and modulation of DC maturation and function.
There are several inhibitory cytokines which modulate Treg and leads to the suppression of effector T cells. It is known that IL-10 and also TGFβ play an important role within the Regulation of the immune response by Treg. If these cytokines are essential for the Treg-derived modulation of the immunity remains controversial. Unlike in vitro studies in vivo studies has shown that a decreased concentration of IL-10 could lead to increased inflammation and hyper-reactivity during allergic diseases. IL10 interacts with and down regulates the expression of NF-κβ. This leads to a decreased differentiation of Th1, Th2 and CD8+ cells. It is important to mention that the depletion of Treg-derived IL-10 do not lead to autoimmunity but could enhance the pathology in the colon and the lung. There is also evidence that the microenviroments of a tumour leads to a increased release of IL-10 by Treg. This results in a increased suppression of the immune response against cancer.
The second type of suppression is caused by cytolysis. Activated regulatory T cells express granzyme A and the Treg-mediated elimination of the target is caused by granzyme A and Perforin through the adhesion of CD18. It also known that Treg express granzyme B. If Treg fails to produce granzyme B the suppression activity is decreased. Treg also suppress the immune response against tumours while Treg kills NK cells and CTLs in a granzyme B- and perforin-manner. There are other apoptosis-inducing ways to suppress the immune system by Treg. One example is the TRAIL-DR5 or the galectin-1 pathway.
A further way to suppress the immune system by Treg is by metabolic disruption of the effector T-cell target. It remains to definitely determine if Treg could grab IL-2 through the high expression of CD25. This would result in a local depletion of IL-2. Dividing effector T cells rely to IL-2 and undergoes apoptosis in the absence of IL-2. But this phenomenon is not the only requirement for Treg to suppress effector T cells. There are further mechanisms like the release of adenosine nucleosides from Treg. These nucleosides activate the adenosine receptor A2AR and suppress the effector T cells. Simultaneous the binding of adenosine nucleosides to A2AR enhance the formation of Treg by inhibiting the expression of IL-6. The formation will be supported by the enhanced secretion of TGFβ. A third metabolic disruption mechanism is the direct transfer of cAMP from Treg to effector T cells via gap junctions.
The fourth mechanism of suppression is the impact of dendritic cells (DC). It is proposed that the expression of cytotoxic T-lymphocyte antigen 4 (CTLA4) by Treg leads to a reduced reactivity of DC when CTLA4 interacts with CD80 and/or CD86 expressed on DC. A further molecule which suppress effector T cell is the 2,3-dioxygenase. This molecule will be secreted when Treg interfere with DC and leads to the production of pro-apoptotic factors. Many other suppressing mechanisms via dendritic cells are known.
It is also important to mention that it will be suggested that Treg need cell-cell-contact for their suppression ability. Nevertheless it should be possible for Treg to supress effector cells just in proximity with high concetrations of supression mediators such as IL-2. Currently it is not known how much the regulation of the immune response by Treg is via antigen presenting cells (APC) such as DC or directly via effector T cells. In vivo studies have shown that Treg are more found in proximity of DC than effector T cells. More investigations is needed to understand the primary target of Treg and how the regulation by Treg happened.
