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.
The mechanisms by which the regulatory T cell activity may be enhanced:
Different therapeutic ways can be designed to modulate the immune responses. Many models are used for expansion and isolation of Tregs in vitro and in vivo.
I.First Pathway is where the drugs are used. These drugs target specific Treg receptors and hence the biochemical pathways are developed.
II.Second pathway is to isolate and expand polyclonal and antigen specific Tregs for immunotherapy.
I.PATHWAY 1: Here the Tregs are targeted in vivo
Polyclonal antibody therapies seem to be an effective way to target Tregs in vivo. These are helpful however there is adverse heterogeneity and xenogenicity seen which might cause side effects. In vivo treatment is long lived and they restore the immune homeostasis. There was an increase in Treg function and selective reduction in pro inflammatory interferon γ production with concomitant increase in suppressive cytokines including IL-10.
Anti CD52 increases reconstitution of Tregs and an anti CD4RO/RA mAb in development promotes Treg development. All of these methods work to enhance the Treg activity by selective depletion of T effector cells. Anti CD28 therapy is an indirect approach to enhance Treg activity however there are other consequences. Rapamycin a drug which binds to FK506 binding protein blocks cell cycle progression and cytokine signal transduction. This promotes Treg development combination of IL-2 and rapamycin leads to a two pronged approach.
A. APC Therapies: The DCs here are also helpful in inducing Tregs in vivo.
There is use of novel markers CD101. We can separate CD11c+ DCs into 2 subsets:
i. One promoting Th1 and Th17 developments
ii. Other Promoting Tregs.
Indolamine 2, 3 dioxygenase, heme oxygenase I and histone deacetylase inhibitors all of them are associated with everything like allograft rejection.HDAC-9 is a histone inhibitor which plays a role in Treg development and function.
II. PATHWAY 2: Expanding Tregs in vitro for immunotherapy
Short term immune regulation of T cells can have long term effect on disease progression. Many of the immunoregulatory drugs induce subsets of Tregs and this gives rise to lifelong efficacy. Antigen specific Tregs are more effective in several autoimmune syndromes compared to polyclonal populations. Absence of IL2 provided by these mature DCs are capable of inducing Ag-specific Treg expression. Gene therapy techniques are very helpful to exapand the Treg population. Expansion of Tregs is done by coating anti-CD3 and anti-CD28 in media with large amounts of recombinant human IL-2. Adding IL-10, dexamethasone and retinoic acid activators all enhance Treg activity.
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