It has been a misunderstanding that allergies and autoimmune diseases are caused due to imbalance in Th1/Th2 activity but this is due to the T regulatory cells (Tregs). The T regulatory cells were first named as suppressor cells as they suppress activation of the immune responses hence maintaining homeostasis and tolerance to self antigens. Foxp3 is a marker found in association with Treg cells. This is an exclusive marker of natural T regs. They can determine origin and development pathway of Treg cells in humans. A mutation in this gene causes inflammation disorders of scurfy in mice and IPEX syndrome in humans.
There are mainly two types of regulatory cells and they are:
1. Natural T regulatory cells
2. Induced T regulatory cells
Natural T regulatory cells are CD4+ CD25+ cells and these contribute 5-10% of the T regulatory population. These natural Tregs are evolved from the thymus and these suppress the response against antigen. Natural Tregs are recognised by constitutive expression of CD4 and CD25 and are defined by transcription factor Foxp3 and surface CD152. Their suppression and generation is expressed or dependent on TGF-β.
Another main type of T regulatory cells is the one which are developed in the thymus but the suppression activity occurs in the periphery of the thymus. This regulates responses not only against self but also non self antigens.
These are called as induced T regulatory cells. Induced T regulatory cells are further classified into two types:
a)Th3 Cells: These were described by Weiner and co workers as CD4+ T cells and these produce TGF-β and varying amounts of IL-4 and IL-10. These were first identified because of their role in oral tolerance through secretion of TGF- β.
b)Tr1 and Tr cells: Chronic activation of both human and murine CD4+ T cells in the presence of IL-10 gave rise to Tr1 cells a subset of CD4+ T cells. Tr1 cells have low proliferative capacity and produce high levels of IL-10, reduced levels of IL-2 and no IL-4.
Tr1 cells can thus regulate antigen specific immune responses and inhibit function of pathological auto antigen specific for T cells and Th2 cells in vivo. Both of these attack antigens but in a non specific way based on cell to cell contact or by release of suppressive cytokines like TGF- β or IL-10.
Naturally occurring CD4+CD25+ T cells are thymus derived and these play a role in innate and adaptive immunity. Some of the markers expressed by these cells are CTLA-4 (cytotoxic T lymphocyte) and glucocorticoid induced tumour necrosis factor receptor. Both of these molecules are expressed by non regulatory T cells after activation. Foxp3 can be upregulated on non regulatory T cells which have been reported but however there have been no clear cut idea regarding this. CD4+CD25- cells from TCR transgenic mice on recombination of activating gene (RAG-2) deficient background which do not contain thymic derived regulatory T cells develop into CD4+CD25+ Treg cells in periphery and upregulate foxp3 expression. TCR signalling is needed for T cell lineage commitment during thymocyte development. There is a difference of thymocytes bearing class I restricted TCRs and difference of thymocytes bearing MHC II restricted TCRs. Small numbers of T cells expressing endogenously rearranged TCR α and TCR β chains prevent autoimmunity in TCR transgenic mouse model. A specific function for TCR ligand interactions helps in development of Treg cells and is supported by increase in Treg cells and these develop in TCR transgenic mice and TCR ligand interactions are needed for development of Treg cells. This occurs mainly in CD4+ T cell lineage and this is thought to be favoured by TCR signals. Costimulatory molecules like CD80 and CD86 are very essential for shaping Treg cell compartment. Treg cell commitment can be facilitated by cytokine signals. CD28 and IL2 have a considerable effect on the development of Treg development. DCs help send signals and stimulate natural tregs to be expressed in the periphery.
Mechanism and suppression by Tregs:
T regulatory cells are very essential for the modulation of immune responses. There are four basic modes of action namely:
1. Suppression by inhibitory cytokines:
Inhibitory cytokines like interleukin 10 and TGF- β have been mediators of Treg cell induced suppression. It was always thought that Tregs function in a contact dependent manner hence the involvement of IL10 and TGF β was thought twice about. Tregs control disease in a manner that is dependent on IL10 and TGF β. An allergen challenge occurs after which CD4+ effector T cells are stimulated and these produce large amounts of IL-10 in lung by allergen specific Tregs and these control diseases. TGF β can mediate suppression by Treg cells in a cell-cell contact dependent manner. TGF β associated with tumour exosome membrane appears to enhance suppressive function of Tregs and take the cells towards regulatory functions. IL35 is needed for suppressive activity. These are said to suppress cell types like DCs and macrophages.
2. Suppression by cytolysis:
Cytolysis mediated through secretion of granzymes had been considered for a long time. Many CD4+ cells express cytotoxic activity. Activated human naturally occurring Treg cells express granzyme A. Treg cells have reduced suppressive activity in vitro and the granzyme B dependent suppression is perforin independent which suppress B cell function. Tregs show suppression of NK cells and CTLs to clear tumours.
3. Suppression by metabolic disruption
There is expression of ectoenzymes CD39 and CD73 which generate pericellular adenosine which suppressed effector T cell cleft function through activation of adenoisine receptor 2A. Adenosine binds to A2aR and this inhibits T cell effector functions and generated induced Treg cells by inhibiting IL-6 expression while promoting TGF β secretion.
4. Suppression by targeting Dentritic cells:
Tregs might also modulate the maturation and function of DCs which are needed for activation of effector T cells. There is a direct interaction seen between Tregs and DCs in vivo. CTLA4 is constantly expressed by Treg cells.
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