Regulatory T cell

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Regulatory T cells ( T Reg ), formerly also known as suppressor T cells , are a specialized subgroup of T cells . They have the function of suppressing the activation of the immune system and thereby regulating the immune system's self-tolerance . In this way, you prevent the development of autoimmune diseases in a healthy organism . Regulatory T cells are found in vertebrates that have an adaptive immune system .

Characterization of regulatory T cells (T Reg )

Immune responses are designed both quantitatively and qualitatively to achieve optimal defensive performance. The aim is to successfully combat a wide variety of pathogens, keep the natural tendency towards autoimmunity under control, and make the lymphocyte effector populations available in sufficient numbers and functional through homeostatic processes. The control mechanisms on which these tasks are based are complex and include different mechanisms for the regulation of autoreactive T cells. These include the deletion of peripheral T cells, the differential mode of action of the cytokines IL-10 and TGF-β , the competition for antigens, growth or differentiation factors, the limitation of clonal expansion through activation of CTLA4 and the induction of programmed cell death via Fas / FasL -mediated signals.

In recent years, there has also been increasing evidence that regulatory T cells may play a central role in limiting an immune response to foreign antigens and in maintaining tolerance to self-antigens. Due to specific markers and special cytokine profiles, regulatory T cells can be phenotypically and functionally divided into different subpopulations (CD4 + -CD25 + T-reg cells, T H 3 lymphocytes and NKT cells).

Types of regulatory T cells (T Reg )

CD4 + -CD25 + T-reg cells

The first population of regulatory T cells arises naturally in the thymus ( natural occuring T regs ). These cells have so far been identified using the surface markers CD4 and CD25 (α chain of the IL-2 receptor). However, CD4 can also be found on T helper cells and CD25 is also found on the surface of other T cells after they have been activated as part of an immune response. After stimulation, these regulatory T cells, which are described as CD4 + -CD25 + - can produce the cytokines IL-4, IL-10 and TGF-β, which are probably not exclusively, but in part, made responsible for the regulatory effector function. In-vitro studies show that CD4 + -CD25 + T cells are themselves anergic and can only be activated for proliferation when IL-2 is added and correspondingly stimulated via the T cell receptor . The in vitro function of immune regulation in these cells is independent of the production of IL-10 and TGF-β, but this requires direct cell-cell contact, although it has not yet been sufficiently clarified whether this contact is first between antigen-presenting cells or whether the regulatory T cells can associate directly with naive T cells.

The T Reg cells are now identified through the expression of the transcription factor FOXP3 ( forkhead box protein 3 ). Furthermore, regulatory T lymphocytes can also be differentiated by the lower expression of the interleukin-7 receptor (IL-7R, CD127) compared to helper lymphocytes that carry the IL-7 receptor on the cell surface. This detection has the advantage over the FOXP3 measurement that the marker is localized on the cell membrane and not intracellularly like FOXP3 and can therefore be stained more easily.

A new analysis method for T Reg cells, which can be used in blood as well as in tissue samples, is based on a T Reg -specific epigenetic marker, more precisely a certain DNA methylation pattern in the area of ​​the FOXP3 gene. The high expression of FOXP3 in T Reg cells is associated with demethylation of the T reg specific region (TSDR). This demethylation is absolutely specific for T Reg cells and has not yet been observed in any other cell type - including human effector T cells which show transient Foxp3 expression after activation. The demethylation is detected at the DNA level, e.g. B. by treating the isolated DNA with bisulfite and then quantitative PCR (see also DNA methylation , epigenetics ).

CD4 + - T regs are more common in ascites and tumor lesions. There they suppress T-cell activation.

CD8 + - T Regs are memory cells that suppress tumor-associated dendritic cell function. They also suppress T cell activation by producing IL-10.

The production of the enzyme indolamine-2,3-dioxygenase by dendritic cells is central to the activation of this type of T Reg cells .

T R 1 cells

A second population of regulatory T cells arises in the periphery and secretes IL-10, IFN-γ, TGF-β and IL-5, but no IL-2 or IL-4. This cytokine pattern allows T R 1 cells to be differentiated from non-polarized (type 0) and polarized (type 1 and 2) T cells. After activation via the T cell receptor, T R 1 cells proliferate only to a limited extent, which is attributed to the autocrine formation of the suppressive cytokine IL-10. This fact is then mainly responsible for why T R 1 cells have so far only been insufficiently characterized. It is known that T R 1 cells can suppress both a type 1 and a type 2-directed immune response through the secretion of TGF-β and / or IL-10. This influence on the activation and proliferation of antigen-stimulated, naive T cells can be neutralized by neutralizing antibodies against TGF-β and IL-10 and is therefore independent of direct cell-cell contact . Furthermore, T R 1 cells inhibit antibody production by B cells and the ability to efficiently present antigen by monocytes and dendritic cells. These different, predominantly in vitro established functions are also held responsible for the suppressive in vivo activity of the T R 1 cells. T R 1 cells develop from naive T cells, whereby the local cytokine environment (including TNF-α IL-10 and probably other cytokines) and the maturity status of the antigen-presenting cells have a decisive influence on the T cell Antigen receptor-mediated activation of T R 1 cells leads.

Type 3 T helper cells (T H 3 lymphocytes)

The exact functions of the T H 3 cells are not yet fully understood. This population of regulatory T cells also arises in the periphery of the immune system. Antigens that are absorbed through the gastrointestinal tract usually lead to a limited T-cell activation without an actual immune response . This observation is explained by the phenomenon of oral tolerance . T H 3 cells which secrete sufficient amounts of immunosuppressive cytokines (mainly the growth factor TGF-β, IL-4 and IL-10) seem to take on regulatory functions.

NK T cells

NK T cells differ from the T cell populations discussed above in several ways. The presence of a T cell receptor clearly identifies them as T cells, but they carry (at least in certain mouse strains) a surface marker that is actually typical for NK cells - hence their name. A number of different subpopulations are summarized under the name NK-T cells, the common feature of which is that their activation is not triggered by classic MHC complexes. These subpopulations are divided according to their phenotype and function; they can carry CD8 or CD4 or be negative for both coreceptors and have both lytic and regulatory activities. The subpopulation of the invariant NK-T , whose TCR always consists of an invariant α-chain in combination with three different β-chains, is best characterized . This TCR binds to an MHC-like molecule, CD1d , which, unlike the classic MHC complexes, does not present peptides, but glycolipids . A glycolipid that is presented via CD1d and is often used as a model antigen is α-galactosylceramide , which was originally isolated from a sponge and attracted attention because of its strong anti-cancer effect. If iNKT cells recognize α-galactosylceramide presented by dendritic cells, a massive release of the cytokines IL-4, IFN-γ and IL-10 occurs within a few hours. This leads to a strong activation of further immune cells (dendritic cells, T and B cells, NK cells) and directs the course of the triggered immune response in a humoral or cellular direction, depending on the circumstances. The number of iNKT cells can multiply after activation (maximum amount after about three days) and then fall back to their original size after one to two weeks. There is no formation of memory cells, actually a characteristic of the adaptive immune response.

NK-T cells thus combine properties of the adaptive and the innate immune system: the presence of a T cell receptor on the one hand and the lack of control by classic MHC complexes and the very rapid release of cytokines on the other. Their ability to direct an immune response in the humoral direction has had a positive effect on the course of autoimmune reactions in the animal model . In humans, too, the administration of α-galactosylceramide has led to promising results in the first preclinical studies , so there is hope of developing a therapy for autoimmune diseases on the basis of this substance.

CD8 + regulatory cells

In addition to the regulatory T cells already mentioned, other T cell populations are also known which exert a suppressive effect, primarily documented in vitro, on the activation of naive T cells. The CD8 + CD28 - T cells generated by repeated antigen stimulation in vitro seem to be able to exert an inhibitory function via their direct cell-cell contact and independently of the cytokines they secret. They have a regulatory influence on antigen-presenting cells and block their upregulation of CD80 / CD86 , CD54 and CD58 . The molecular mechanism on which this inhibition is based causes the activation of the T-cell permanent receptors ILT3 (immunoglobulin-like transcript) -3 and ILT4. These molecules, which are related to KIR ( killer cell inhibitory receptor ), have an inhibitory effect on cell activation through the subsequent inclusion of SHP1 phosphatase . While the ligand for ILT3 is still unknown, ILT4 binds to HLA-A, -B, -C , and -G on the surface of antigen-presenting cells and modulates the signals transduced via CD40 and other coreceptors so that sufficient T- Cell activation fails. Another population of regulatory CD8 + T cells can be generated in vitro by stimulation with CD40-activated, plasmacytoid dendritic cells. These regulatory CD8 + T cells have limited cytotoxicity , secrete predominantly IL-10 and have phenotypic features which are similar to regulatory T R 1 cells.

history

The existence of regulatory T cells has long been controversial. As early as the 1970s, various research groups - including those of Richard K. Gershon - reported on suppressor T cells that were able to suppress autoimmune responses. In the 1980s and 90s the concept was questioned because data were not reproducible and the molecular mechanisms remained unknown.

Only since the mid-1990s have T Regs been reliably described and the mechanisms of action have been partially clarified.

literature

Individual evidence

  1. ↑ G. Wieczorek et al .: Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. In: Cancer Res. (69), 2009, pp. 599-608. PMID 19147574 ( reference list for epigenetic Treg analysis )
  2. ^ W. Chen, X. Liang, AJ Peterson, DH Munn, BR Blazar: The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation . In: J. Immunol . tape 181 , no. 8 , October 2008, p. 5396-5395 , PMID 18832696 .
  3. ^ L. Van Kaer: alpha-galactosylceramide therapy for autoimmune diseases: prospects and obstacles . In: Nature Reviews Immunology . tape 5 , no. 1 , 2005, p. 31-42 , PMID 15630427 .