Regulatory T cell
Regulatory T cells ( TReg ), previously also called suppressor T cells, are a specialized subgroup of the T cells. They have the function to suppress the activation of the immune system and thereby regulate the self-tolerance of the immune system. This will prevent the healthy organism, the development of autoimmune diseases. Regulatory T cells are found in vertebrates that possess an adaptive immune system.
Characterization of regulatory T cells ( TReg )
Immune responses are both quantitatively and qualitatively interpreted on achieving an optimal defensive performance. Thus, the variety of pathogens want to successfully combated, kept the natural tendency to autoimmunity under control and the lymphocyte effector populations are provided by homeostatic processes in sufficient number and functional. The control mechanisms which are based on these tasks are complex and include the regulation of autoreactive T cells different mechanisms. These include the deletion of peripheral T - cells, the differential effect of the cytokines IL -10 and TGF- β, the competition for antigens, growth or differentiation factors, the limitation of the clonal expansion by activation of CTLA4, and the induction of programmed cell death via Fas / FasL -mediated signals.
In recent years, additional evidence has accumulated that even so-called regulatory T cells could be centrally involved in the limitation of an immune response against foreign antigens and in the maintenance of tolerance to self - antigens (formerly also suppressor T - cells). Due to the specific markers and cytokine profiles specific regulatory T cells can be divided into both phenotypically and functionally different subpopulations ( CD4 CD25 T- reg cells, TH3 lymphocytes and NKT cells ).
Types of regulatory T cells ( TReg )
CD4 CD25 T reg cells
The first population of regulatory T cells arises naturally in the thymus (natural occuring T regs ). These cells have been identified on the basis of surface markers CD4 and CD25 ( α - chain of the IL -2 receptor ). CD4 is, however, also found on T helper cells and CD25 is also found on the surface of other T cells after their activation in the context of an immune response. After stimulation, this can be used as the CD4 CD25 - are the cytokines IL -4, IL -10 and TGF, which are probably not limited to, but made in part responsible for the regulatory effector circumscribed regulatory T cells. In vitro studies demonstrate that CD4 CD25 T cells are anergic itself and can be activated only with the addition of IL-2 and the appropriate stimulation via the T cell receptor to proliferate. The in vitro function of immune regulation, in these cells independently of the production of IL -10 and TGF, but it requires this of a direct cell-cell contact, without would be that but already sufficiently clarified whether this contact first to between antigen-presenting cells has made or whether the regulatory T cells can directly associate with naive T cells.
The T- reg cells are now identified by the expression of the transcription factor FOXP3 ( forkhead box protein 3). In addition, regulatory T - lymphocytes can also be due to the lower expression of the interleukin -7 receptor ( IL- 7R, CD127 ) differ compared to helper lymphocytes bearing the IL-7 receptor on the cell surface. This proof has the advantage that the marker on the cell membrane and is not localized, intracellular FOXP3 and therefore be stained lighter than the FOXP3 measurement.
A new analysis method for T- reg cells, which can be applied both in blood and in tissue samples based on a Treg - specific epigenetic Maker, more precisely a specific DNA methylation patterns in the area of the foxp3 gene. The high expression of Foxp3 in Treg cells is accompanied by demethylation of Treg -specific region ( TSDR ). This demethylation is absolutely specific for Treg cells and has been until now in any other cell type - including human effector T cells, pointing to the activation of a transient Foxp3 expression - observed. The detection of the demethylation is carried out at the DNA level, for example by treatment of the isolated DNA with bisulfite and subsequent quantitative PCR (see, DNA methylation, epigenetics ).
CD4 - Tregs are increasingly present in ascites and tumor lesions. They suppress where the T- cell activation.
CD8 - Tregs are memory cells that suppress tumor-associated dendritic cell function. In addition, they suppress the T-cell activation by IL- 10 production.
Central to the activation of this type of T- reg cells is the production of the enzyme indoleamine -2 ,3- dioxygenase by dendritic cells.
TR1 cells
A second population of regulatory T cells is generated in the periphery and secreted IL -10, IFN- γ, TGF- β and IL- 5 but not IL-2 or IL-4. Cells of non -polarized ( type 0 ) and polarized ( type 1 and -2) T- cells are differentiated - by this Zytokinemuster TR1 can. TR1 - cells proliferate upon activation through T cell receptor only in a limited extent, which is attributed to the formation of the autocrine suppressive cytokine IL- 10 action. This fact is then primarily responsible for why TR1 cells could be characterized so far only insufficiently. It is known that both TR1 cells can suppress type-1 and type-2 immune response directed by the secretion of TGF- β and / or IL-10. This influence on the activation and proliferation of antigen- stimulated naive T cells can be reversed by neutralizing antibodies to TGF- β and IL- 10, and is therefore independent of direct cell-cell contact. Further, Tr1 cells inhibit antibody production by B cells and the ability for efficient antigen presentation by monocytes and dendritic cells. These different functions can be established in vitro predominantly responsible for the in vivo suppressive activity of Tr1 cells. TR1 cells develop from naive T cells, the local cytokine milieu (including TNF- α, IL-10 and probably other cytokines ) and the maturation state of antigen -presenting cells have a decisive influence on whether the T- cell antigen receptor TR1- mediated activation of cells.
Type 3 helper T cells (TH3 - lymphocytes)
The exact function of Th3 cells are not yet fully understood. These population of regulatory T cells is generated in the periphery of the immune system. Antigens, which are absorbed from the gastrointestinal tract, usually lead to a limited T cell activation without there being a proper immune response. This observation is explained by the phenomenon of oral tolerance. Th3 cells which sufficient amounts of immunosuppressive cytokines ( primarily the growth factor TGF- β, IL-4 and IL-10 secreting regulatory functions seem to take.
NK - T cells
NK T cells differ in several respects from the above- treated T -cell populations. The presence of a T- cell receptor, it has clearly than T- cells, but they wear ( at least in certain mouse strains ) a typical actually for NK cell surface markers - so stirred her name. Under the name of NK T cells a number of different subpopulations are grouped together, their common feature is that their activation is not triggered by classical MHC complexes. These subpopulations are divided according to their phenotype and function; they may CD8 or CD4 wear or be negative for both co-receptors, and exhibit both lytic and regulatory activities. The best characterized is the subpopulation of invariant NK T whose TCR always consists of an invariant α - chain in combination with three different β - chains. TCR that binds to a MHC - like molecule CD1d, which does not present the peptides glycolipids but in contrast to the classical MHC complexes. A CD1d -presented above, is frequently used as a model antigen α - galactosyl glycolipid, which was originally isolated from a sponge and noticed because of strong anti-cancer effect. Recognize iNKT cells -presented by dendritic cells α - galactosylceramide, it comes within a few hours to a massive release of cytokines IL -4, IFN- γ and IL-10. This results in a strong activation of other immune cells (dendritic cells, T cells and B cells, NK cells ) and directs the course of the immune response induced in a - depending on the circumstances - humoral or cellular stressed direction. The number of iNKT cells can multiply after activation ( maximum amount after about three days ), and then drops after a week or two back to the original size. This occurs no formation of memory cells actually a feature of the adaptive immune response.
Thus, NK - T cells combine properties of the adaptive and innate immune system: the presence of a T- cell receptor on the one hand and the lack of control by classical MHC complexes and the very rapid cytokine secretion on the other side. Your ability to direct an immune response in the humoral direction has a positive effect in the animal model on the course of autoimmune responses. In humans, the administration of α - galactosylceramide has resulted in the first preclinical studies on promising results, so the hope is to develop on the basis of this substance a therapy for autoimmune diseases.
CD8 regulatory cells
In addition to the above-mentioned regulatory T cells also other T-cell populations are known which exert a mainly documented in vitro suppressive effect on the activation of naive T cells. Thus, by repeated antigen stimulation in vitro generated CD8 CD28 seem - T cells via their direct cell -cell contact and to be able to exert an inhibitory function independent of their secreted cytokines. They take on regulatory antigen -presenting cells and block their influence upregulation of CD80/CD86, CD54 and CD58. The molecular mechanism that underlies this inhibition to reason, caused the activation of T -cell -bound receptors ILT3 ( immunoglobulin -like transcript ) -3 and ILT4. This KIR (killer cell inhibitory receptor ) related molecules act on the downstream involvement of SHP1 phosphatase inhibitory to cell activation. While the ligand for ILT3 is still unknown, ILT4 to HLA-A, -B,- C and -G binds to the surface of antigen-presenting cells and modulates the CD40 and other coreceptors transduced signals, so that a sufficient T cell activation fails. A further population of CD8 regulatory T cells can be generated in vitro by stimulation with CD40 -activated plasmacytoid dendritic cells. These regulatory CD8 T cells have a reduced cytotoxicity secrete predominantly IL-10 and possess phenotypic characteristics, which regulatory Tr1 cells are similar.
History
The existence of regulatory T cells has long been controversial. Already in the 1970s, reported several research groups - including those of Richard K. Gershon - could suppress of suppressor T cells, the autoimmune responses. In the 1980s and 90s, the concept has been questioned, because data were not reproducible and the molecular mechanisms remain unknown. Only since the mid-90s Tregs were reliably described and the mechanisms of action have been partially elucidated.