Immune tolerance is a state in which the immune system does not react specifically to certain antigens. It can be divided into two stages: central immune tolerance and peripheral immune tolerance. Central immune tolerance is a thymus-dependent process that eliminates autoreactive clones (i. e. , negative selection) by inducing apoptosis; Peripheral immune tolerance can be subdivided into at least three types: clonal clearance, immune anergy, and Suppressive State, of which the first two are collectively referred to as recessive tolerance. In recent years, studies have shown that regulatory cellular mechanisms can be used to induce graft immune tolerance and induce long-term graft survival without the use of immunosuppressants, this natural immunoregulatory mechanism is called regulatory cell-mediated immune tolerance. T cell subsets that specifically regulate suppressive processes, known as Regulatory T Cells (Tregs) , have been identified, with CD4 + CD25 + Foxp3 + Tregs being the most studied. In addition to regulatory T cells, regulatory cells also include regulatory B cells and regulatory DC cells.
Foxp3 + Tregs account for 5-10% of peripheral CD4 + T cells in mice and humans and are essential for maintaining immune homeostasis. Tregs are divided into two categories: thymus-derived (natural) Tregs (tTregs or nTregs) and inducible (adaptive) peripheral Tregs (iTregs or pTregs) . nTregs are produced in the thymus, and most express the IL-2 receptor α-chain (CD25) , whose development and function depend on the expression of the transcription factor FOXP3; whereas iTregs are produced in the periphery, and nTregs are produced in the periphery, and under the stimulation of specific antigen derived from the initial T cells.
Tregs are subjected to both positive and negative selection during thymic development. It is currently thought that the t-cell receptor (TCR) of developing thymocytes has a moderate affinity for MHC and self-peptides, can be induced to express FOXP3 and differentiate into tTregs, and that the t-cell receptor (TCR) of developing thymocytes can be induced to express FOXP3 and differentiate into tTregs, it is critical in suppressing autoreactive T cells that escape negative selection. In contrast, ptregs are induced in the periphery by Na? Ve T cells. In vitro, high concentrations of TGF-β stimulate T cells to produce such inducible Tregs. Other factors that promote Treg generation include vitamin D, retinoic acid, vitamin C, and inhibition of Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI-3K) activity.
With the improvement of detection technology and further studies, the phenotype and function of Tregs vary with the immune environment. All CD4 + T cells can be classified into 3 subsets based on the expression of CD45RA and Foxp3: quiescent/naive Tregs (CD45RA + Foxp3 +) , effector/activated Tregs with higher expression levels of KI67 and CTLA4(CD45RA-FOXP3 + + +) , and non-suppressive T cells secreting cytokines such as IL-2, IFN-γ, and Il-17(CD45RA-FOXP3 +) . Compared with non-suppressive T cells, Foxp3 functions more strongly in quiescent and activated Tregs, and Foxp3 regions are mostly demethylated.
There may be interconversion between Tregs and other CD4 + T cells, which is essential for the function and stability of Tregs. Epigenetics ttregs, especially Treg-specific demethylated region (TSDR) demethylation, are more difficult to convert to other CD4 + T cell phenotypes; Whereas TSDR unmethylated ptregs (or itregs) seem to be more easily converted to the pathogenic subtype of CD4 + T cells. In addition, several factors that promote Treg stability, including retinoic acid, Sirolimus, and IL-2, have now been used to expand Tregs in vitro.
On the one hand, Tregs can suppress the excessive immune response, thereby reducing the occurrence of autoimmune diseases; on the other hand, they can alleviate graft-versus-host disease. It is now well established that Tregs play a key role in allograft tolerance. In several mouse model studies involving allografts of the skin, islets, heart, and kidney, Tregs were able to suppress the activity and function of effector T cells, leading to allograft tolerance. Miyajima M et al. 1 have shown that mice exhibit tolerance to kidney allografts without immunosuppression in some cases of complete MHC incompatibility. This tolerance initially depends on Foxp3 + cells, which cluster in Tregs-rich tissue lymphoid structures in the graft and may inhibit the maturation of DCs. In addition to mice, in pigs and nonhuman primates, kidney allograft recipients develop tolerance to skin and heart transplants from the same donor. Liao T et al. 2 showed that infusion of iTregs in mice significantly alleviated the injury and rejection of transplanted kidneys and significantly improved the survival of kidney allografts. Since ITREG treatment reduces the levels of donor-specific antibodies as well as the cell infiltration involved in the process of antibody-mediated rejection (Amr) , it is promising to use iTregs to prevent AMR in the clinic.
References:
[1] Miyajima M, Chase C M, Alessandrini A, et al. Early Acceptance of Renal Allografts in Mice Is Dependent on Foxp3+ Cells[J]. The American Journal of Pathology, 2011,178(4):1635-1645.
[2] Liao T, Xue Y, Zhao D, et al. In Vivo Attenuation of Antibody-Mediated Acute Renal Allograft Rejection by Ex Vivo TGF-β-Induced CD4+Foxp3+ Regulatory T Cells[J]. Frontiers in Immunology, 2017,8.
文 | 林荣辉 插图 | Lily Zhou
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