The role of regulatory T cells in the autoimmune system
In the 1970s, regulatory T cells (Treg), a type of T cell with immunosuppressive properties, were identified and have become a hot topic of research in the field of immunology in recent years. A review of the literature on the role of regulatory T cells (Treg) in the autoimmune system is presented.
1. Classification and function of regulatory T cells
Regulatory T cells can be divided into naturally occurring natural regulatory T cells (nTreg) and induced adaptive regulatory T cells (aTreg or iTreg), such as Th3 and Tr1, as well as CD8 Treg and NKT cells, which are closely related to the development of autoimmune diseases and their abnormal expression can lead to autoimmune diseases.
1.1 Natural regulatory T cells (nTreg)
The main ones are CD+4 CD+25 Treg. Sakaguchi et al [1] transferred T cells from CD+4 CD+25 Treg-deficient mice to nude mice resulted in various autoimmune diseases, while pre-infusion of CD+4 CD+25 Treg prevented the occurrence of such diseases; transferring CD+4 T cells from the spleen of normal mice with CD+25 cells removed to homozygous T CD+4 CD+25 Treg accounts for approximately 5% to 10% of CD+4 T cells in peripheral blood and spleen. In addition to expressing CD4 and CD25 molecules, CD+4 CD+25 Treg is characterized by its high expression of the transcription factor Foxp3, which not only serves as a marker molecule for CD+4 CD+25 Treg, but is also a key gene in determining the function of CD+4 CD+25 Treg. disease is very similar to the X-chromosome-linked autoimmune allergic dysregulation syndrome (XLAAD) disease in humans, and Foxp3-/- mice do not display CD+4 CD+25 Treg activity.CD127 also serves as a specific marker for this population of cells, and there is a good correlation between high Foxp3 expression and low CD127 expression, i.e., the cell population of Foxp3 is CD -127 CD+4 CD+25 Treg secretes TGF-β and IL-10, two cytokines that correlate with their immunomodulatory functions [2].
1.2 Adaptive regulatory T cells (aTreg or iTreg)
It is developed from peripheral naïve T cells induced by small doses of antigen or immunosuppressive cytokines, including Tr1, Th3 and other cells, which mainly secrete IL-10 and TGF-β to play immune negative regulatory roles.
(1) Tr1-type CD+4 regulatory T cells: In vitro stimulation of antigen-specific CD+4 T cell clones with IL-10 results in a population of CD+4 T cells with a cytokine phenotype distinct from that of Th1 and Th2 cells [3]. This population, which secretes mainly high levels of IL-10, moderate levels of TGF-β and IFN-r and does not secrete IL-4 and IL-2, is known as Tr1 cells. tr1 cells can suppress the proliferative response of naive and memory T cells by secreting IL-10 and TGF-β. When this population is co-infused with CD+4 CD45 RBhi cells into SCID mice, it can prevent the development of autoimmune enterocolitis. Tr1 cells were also found in patients with severe immunodeficiency who received allogeneic stem cell transplantation, similar to CD+4 CD+25 Treg. Tr1 cells also require antigen activation of the TCR to exert regulatory effects, and their inhibition in vivo is dependent on IL-10, and the mechanism of inhibition in vitro may be through intercellular contacts.
(2) Th3 type CD+4 regulatory T cells: it secretes and produces large amounts of TGF-β, which has an inhibitory effect on both Th1 and Th2. Th3 cells can secrete TGF-β and varying levels of IL-4 and IL-10 after antigen-specific activation [4].
1.3 CD+8 regulatory T cells
CD+8 Treg in humans are mainly derived from CD+8 CD-28 T lymphocytes. In vitro studies have shown that IL-10 secreted by monocytes after stimulation with GM-CSF plays an important role in the production of CD+8 Treg. CD+8 Treg has two subpopulations, CD+28 and CD-28, and the more studied one is CD+8 CD-28. CD+8 CD-28 is a Treg with immunosuppressive effects, and is subdivided into 3 types, type I cells through Type I cells alter the expression of dendritic cell costimulatory molecules and exert their suppressive effects through direct contact with dendritic cells; Type II cells exert their suppressive effects through cytokines such as IFN-r and IL-6, which do not require direct contact with antigen-presenting cells; Type III cells exert their suppressive effects mainly through the secretion of IL-10.
1.4 Natural killer T cells (NKT)
It is a unique group of αβ T cells that expresses the T cell receptor TCRαβ, in addition to the NK cell receptor NK1.1 or NK161. NKT activated by NK T cells can, on the one hand, rapidly secrete large amounts of Th2-type cytokines such as IL-4 and IL-10, and secrete IL-13 to regulate CD+8 T cell function, thereby controlling the development of various autoimmune diseases. On the other hand, it can enhance anti-tumor immunity by rapidly secreting IFN-r, TNF and other Th1-type cytokines.
2. The relationship between regulatory T cells and autoimmune diseases
2.1 Regulatory T cells and type I diabetes mellitus
Type I diabetes mellitus (T1D) is a metabolic disorder syndrome caused by the continuous activation of self-reactive T cells and the destruction of pancreatic β cells, resulting in impaired insulin secretion, which is an autoimmune disease. the development of T1D is related to the number and function of regulatory T cells and the imbalance of the ratio of regulatory T cells to effector T cells [5]. However, in most susceptible individuals, environmental factors (microorganisms, chemicals, food, etc.) and genetic abnormalities affect the production of CD+4 CD+25 Treg in the thymus, inhibit its development, alter its regulatory activity, and predispose to the development of autoimmune diseases. CD+4 CD+25 Treg is produced in the thymus and enters the periphery to function, and its long-term presence in the periphery depends on self-antigens and CD- 28 B7, CD-40 CD40L co-stimulatory molecules for chronic stimulation [6]. Blocking the CD-28B7 pathway in non-obese diabetic (NOD) mice can exacerbate autoimmune disease by reducing CD+4 CD+25 Treg. The number of CD+4 CD+25 Treg is reduced in both autoimmune diabetic patients and NOD rats [7], and the abnormal function of this cell is present before the onset of autoimmune diabetes, as evidenced by the inability to inhibit the proliferation of polyclonally activated CD-25Treg in vitro, whose effects may be exerted through the TGF-β pathway.NK T cells cannot prevent the initial activation of pathogenic CD+4 T cells and NK T cells cannot prevent the initial activation and proliferation of pathogenic CD+4 T cells, but they can inhibit their IL-2 and IFN-γ production and late proliferation, thus preventing CD+4 T cells from causing severe islet inflammation and destroying β cells. However, T1D is also an autoimmune disease, and the complexity and diversity of CD+8 Treg suggest that it may play an important role, together with CD+4 Treg, in the control of T1D pathogenesis. Gene locus Idd6 predisposes NO D mice to develop type I diabetes on their own, and a major mechanism by which gene locus Idd6 regulates diabetes onset was found to be through modulation of regulatory T cell activity by using purified splenocytes and purified T cells in transformation experiments [8].
2.2 Regulatory T cells and systemic lupus erythematosus
Regulatory T cells in systemic lupus erythematosus (SLE) are mainly associated with natural regulatory T cells in.
(1) The pathogenesis of SLE may be associated with a decrease in Treg: the number of CD+4 CD+25 Treg in peripheral blood is significantly reduced in patients with SLE, and the number of CD+4 CD+25 Treg in peripheral blood is significantly reduced in patients with active SLE compared to patients with inactive SLE and normal subjects, and the number of CD+4 CD+69 T cells is increased compared to normal subjects [9].The suppression of IL-2 production during active SLE is consistent with the change in the number of T cells The change in IL-2 production during the active phase of SLE is consistent with the change in the number of T cells, thus confirming that CD+4 CD+25 Treg is significantly reduced during the active phase of SLE, and that autoantibodies in the body increase substantially during the onset of SLE, and that CD+4 CD+25 Treg is cleared by its inappropriate induction to apoptosis.
(2) Treg inhibits Th cell activity and B cell function: Treg can inhibit Th cell activity through direct intercellular contact mechanism and cytokine secretion mechanism, thus potentially avoiding the occurrence of SLE.
(3) Treg inhibits dendritic cell (DC) maturation and antigen-presenting function: DC can promote the development of SLE.
(4) IL-10 secreted by Treg inhibits the production of IFN-α: IFN-α induces the production of the antiviral gene products RNA-dependent protein kinase (PKR), oligoadenine nucleotide synthase (OAS), ribonuclease ligand (RNASL), and Mx protein, which are associated with the development of SLE. vigna-Perez et al [10] observed clinical and immunological effects of Rituximab (anti-CD20) used concomitantly with immunosuppressive agents in 22 patients with active lupus nephritis (WHO typing mainly type III and IV), the number of CD+4 CD+25 Treg, Tr1 and Th3 were significantly increased on day 30, suggesting that Tr1 and Th3 are also associated with SLE. the relationship between CD+8, CD-28 Treg and SLE relationship was not reported as much as CD+4 CD+25 Treg. It has been reported that there is no statistically significant difference between the two, either in terms of the level of CD+8 and CD-28 Treg in healthy subjects and SLE patients, or in terms of the level of CD+8 and CD-28 Treg and disease activity [11].
2.3 Regulatory T cells and aplastic anemia
Aplastic anemia (AA) is a relatively common disease of the hematological system characterized by allogeneic cytopenia and bone marrow hematopoietic failure.In AA, abnormal hyperfunction of T cells is an important cause of bone marrow failure due to the direct killing effect of cytotoxic T cells.Treg can inhibit and regulate the activation and proliferation of CD+4 and CD+8 T cells and play a negative regulatory role.Chen et al [ 12] found that the imbalance of inhibitory activation between Treg and T cells led to bone marrow failure, and the fact that the development of AA was reversed after infusion of CD+4 CD+25FOXP+3 T further argued for the role of CD+4 CD+25 Treg in the pathogenesis of AA. Solomou et al [13] demonstrated that the relative and absolute amounts of CD+4 CD+25 Treg as well as CD+4 CD+25 FOXP+3 Treg were lower in AA patients than in healthy subjects. in addition to In addition to a significant decrease in the number of CD+4 CD+25 Treg in the peripheral blood circulation, the expression of FOXP3 and the transcription factor NFAT1 also decreased significantly, with NFAT1 playing a synergistic role in the immunosuppression of CD+4 CD+25 Treg with respect to FOXP3, thus indicating that the abnormal CD+4 CD+25 Treg number and function is one of the important links in the development and progression of AA disease.
2.4 Regulatory T cells and idiopathic thrombocytopenic purpura
Patients with idiopathic thrombocytopenic purpura (ITP) have a variety of T lymphocyte abnormalities, especially dysfunctional and disproportionate T cell subsets, which play an important role in the pathogenesis of ITP [14]. peripheral blood CD+4 T cells and CD+4 CD+25 Treg numbers are lower in ITP patients than in controls, and the CD+4 CD+25/CD+4 ratio is also significantly lower, causing the organism The balance of immune tolerance within the body was disrupted [15]. The decrease in the number of cells and the content of secreted cytokines may lead to a weakening of cellular immunosuppression and a disruption of the autoimmune tolerance balance, with an increase in activated auto-reactive T cells and an increase in platelet destruction; the increased activation of T lymphocytes may also assist B cells in producing more anti-platelet antibodies and an increase in platelet destruction, with symptoms such as thrombocytopenia and skin and mucosal bleeding, suggesting that T cells may play an important role in the pathogenesis of ITP.
2.5 Regulatory T cells and autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) is a group of hemolytic anemias caused by mutations in the immune response in vivo, mainly by abnormal hyperfunction of primary and secondary B cells, which produce autoantibodies or (and) complement that bind to the erythrocyte membrane, resulting in increased erythrocyte destruction. Ward et al [17] found that an IL-10-secreting autoantigen (72H-86L peptide) specific Treg clone was isolated and cultured in a patient with AIHA, which This undoubtedly provides an important theoretical basis for the use of T cells in the clinical treatment of AIHA.
2.6 Regulatory T cells and multiple sclerosis
Multiple sclerosis (MS) is an inflammatory demyelinating disease that occurs in the white matter of the central nervous system (CNS) and is a T cell-mediated autoimmune disease that appears mainly in young adults with a variety of clinical symptoms, including optic neuritis, nystagmus, ocular muscle paralysis, ataxia, paralysis, and spasticity, accompanied by relapses and remissions. The main feature of the pathological damage is the demyelination of myelin sheaths occurring in the white matter of the central nervous system with infiltration of T lymphocytes. Recent studies have demonstrated that although type I helper T cells (Th1) play an important role, other immune cells, including B cells, CD+8 Treg, NKT and CD+4 CD+25 Treg, can also be involved in the pathogenesis of MS patients by inducing or modulating the immune response process within the CNS [18]. Removal of CD+8 Treg from CD28 mice increases the chance of autoimmune encephalomyelitis in these mice, and in addition, the chance of autoimmune encephalomyelitis is significantly higher in mice in which both CD8 and CD28 genes are removed, suggesting that CD+8 Treg plays a role in the pathogenesis of the disease in mice in which CD28 genes are removed [19].MS patients without There is no abnormality in the number of CD+4 CD+25 Treg and there may be altered immune activity to develop autoimmune encephalomyelitis [20].
2.7 Regulatory T cells and inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of autoimmune diseases of unknown etiology that invade the gastrointestinal tract, including ulcerative colitis (UC) and Crohn’s disease (CD), and is currently thought to be associated with the interaction of immune, genetic, and infectious factors, with immune factors playing a key role [21]. In normal intestinal mucosal tissues, effector T cells and regulatory T cells are in a dynamic balance to maintain the stability of the intestinal environment; if effector T cells are overproliferated or immunogenic enhanced, or if regulatory T cells are reduced in number or function abnormally, the balance between them can be disrupted, leading to intestinal mucosal damage and thus inducing the development of inflammatory bowel disease. reduction in the number of CD+4 CD+25 Treg, expression of surface molecules The decrease in the number of CD+4 CD+25 Treg, the deficient expression of surface molecules, and the impaired inhibitory function are all associated with the development of IBD. The mechanisms may be: CD+4 CD+25 Treg acts in direct contact with target cells, downregulating cellular IL-2Ra chain expression such that target cells proliferate; may reduce the inflammatory response by secreting suppressive cytokines; TCR mediates self-reactive T cell recognition of self-peptides, as internal environmental stability is correlated with immune regulation, suggesting that regulatory T cells may work with pathogenic T cells The imbalance between increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory factors in IBD patients is the main cause of pathogenesis. cd+4 cd+25 Treg exerts its immunosuppressive effect by secreting production of anti-inflammatory cytokines IL-10 and TGF-β, blocking and downregulating CD+4 cd+25 Treg cells leading to a pro-inflammatory response. th3 cells inhibit TNBS-induced colitis [22]. It has also been shown that Tr1 has a preventive and therapeutic role in CD+4 CD45 RBhigh-induced IBD and that the immune tolerance effect of CD+4 CD+25 Treg is partly attributed to an indirect action through the differentiation of Tr1 [23]. There is a defect in CD+8 regulatory cells in the intestinal mucosa of IBD patients, as evidenced by a near-absence of the proliferative inhibitory effect of CD+8 regulatory cells in the intestinal mucosa on lymphocytes in vitro and a possible significant decrease in CD8 in TCR Vβ5.1-positive, but not in CD+8 CD-28 Treg [24].
2.8 Regulatory T cells and myasthenia gravis
Myasthenia gravis (MG) is a T cell-dependent, antibody-mediated neurological autoimmune disease in which large amounts of antibodies to acetylcholine receptors (AchRAb) accumulate at the neuromuscular junction and interfere with normal neurotransmitter transmission, leading to myasthenia gravis.Abnormalities in the thymus of MG patients may lead to a decrease in the number and/or malfunction of CD+4 CD+25 Treg, resulting in auto-reactive CD+4 Treg is activated in large numbers to help B cells produce autoantibodies and participate in the pathogenesis of MG. The pathogenesis of myasthenia gravis is associated with defective CD+4 CD+25 Treg phenotype and function [25]. The presence of a high percentage of CD+4 CD+25 Treg expression in the peripheral blood of thymectomized MG patients may be associated with the remission of the disease. MG disease stabilizes or remits when the abnormal thymus is removed and the body is able to produce sufficient amounts of CD+4 CD+25 Treg to counteract self-reactive T cells [26].
Regulatory T cells are also associated with the development of many autoimmune diseases such as rheumatoid arthritis, autoimmune thyroiditis, autoimmune liver disease, and various kidney diseases. Regulatory T cells are important for the occurrence and development of autoimmune diseases, and their in-depth study will help to understand the pathogenesis of autoimmune diseases, which will have far-reaching implications for the prognosis and further treatment of diseases.