October 25, 2024, Immune Tolerance
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 aImmune tolerance is a state in which the immune system does not mount a specific response to certain antigens. It is categorized into two stages: central immune tolerance and peripheral immune tolerance. Central immune tolerance is a thymus-dependent process that eliminates autoreactive clones (i.e., through negative selection) by inducing apoptosis. Peripheral immune tolerance can be subdivided into at least three types: clonal deletion, immune anergy, and a suppressive state, with the first two collectively referred to as recessive tolerance. In recent years, studies have demonstrated that regulatory cellular mechanisms can induce graft immune tolerance and promote long-term graft survival without immunosuppressants; this natural immunoregulatory mechanism is termed regulatory cell-mediated immune tolerance. Subsets of T cells that specifically regulate suppressive processes, known as regulatory T cells (Tregs), have been identified, with CD4+CD25+Foxp3+ Tregs being the most extensively studied. Besides regulatory T cells, regulatory cells also encompass regulatory B cells and regulatory dendritic cells (DCs).
Foxp3+ Tregs constitute 5–10% of peripheral CD4+ T cells in mice and humans and are crucial for maintaining immune homeostasis. Tregs are categorized into two types: thymus-derived (natural) Tregs (tTregs or nTregs) and inducible (adaptive) peripheral Tregs (iTregs or pTregs). nTregs are generated in the thymus, with most expressing the IL-2 receptor α-chain (CD25); their development and function rely on the expression of the transcription factor FOXP3. In contrast, iTregs are generated in the periphery under the stimulation of specific antigens derived from naïve T cells.
Tregs undergo both positive and negative selection during thymic development. It is currently believed that the T-cell receptor (TCR) of developing thymocytes, with moderate affinity for MHC and self-peptides, can be induced to express FOXP3 and differentiate into tTregs, playing a critical role in suppressing autoreactive T cells that escape negative selection. Conversely, pTregs are induced in the periphery from naïve T cells. In vitro, high concentrations of TGF-β stimulate T cells to generate these inducible Tregs. Other factors promoting Treg generation include vitamin D, retinoic acid, vitamin C, and inhibition of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) activity.
With advancements in detection technology and further research, the phenotype and function of Tregs vary depending on the immune environment. All CD4+ T cells can be categorized into three subsets based on the expression of CD45RA and Foxp3: quiescent/naïve Tregs (CD45RA+Foxp3+), effector/activated Tregs with elevated 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 to non-suppressive T cells, Foxp3 exhibits stronger functionality in quiescent and activated Tregs, with Foxp3 regions predominantly demethylated.
There may be interconversion between Tregs and other CD4+ T cells, which is vital for the function and stability of Tregs. Epigenetically modified tTregs, particularly those with Treg-specific demethylated region (TSDR) demethylation, are less likely to convert to other CD4+ T cell phenotypes. In contrast, pTregs (or iTregs) with unmethylated TSDR appear more prone to converting into pathogenic subtypes of CD4+ T cells. Additionally, several factors that enhance Treg stability, including retinoic acid, sirolimus, and IL-2, are now utilized to expand Tregs in vitro.
On one hand, Tregs can suppress excessive immune responses, thereby reducing the incidence of autoimmune diseases; on the other hand, they can mitigate graft-versus-host disease. It is now widely recognized that Tregs play a pivotal role in allograft tolerance. In multiple mouse model studies involving allografts of the skin, pancreatic islets, heart, and kidney, Tregs have been shown to suppress the activity and function of effector T cells, resulting in allograft tolerance. Miyajima M et al. [1] demonstrated that mice can exhibit tolerance to kidney allografts without immunosuppression in certain cases of complete MHC incompatibility. This tolerance initially relies on Foxp3+ cells, which aggregate in Treg-rich lymphoid structures within the graft and may inhibit dendritic cell (DC) maturation. Beyond mice, kidney allograft recipients in pigs and nonhuman primates have developed tolerance to skin and heart transplants from the same donor. Liao T et al. [2] demonstrated that infusing iTregs in mice significantly mitigated injury and rejection of transplanted kidneys, markedly improving kidney allograft survival. Since iTreg treatment reduces levels of donor-specific antibodies and cellular infiltration associated with antibody-mediated rejection (AMR), using iTregs to prevent AMR in clinical settings holds promise.
References:
[1] Miyajima M, Chase CM, 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.
Written by | Lin Ronghui, Illustrations | Lily Zhou This article is an original publication of the “Kidney Transplantation, Zhongshan Hospital, Fudan University” WeChat public account. Reproduction requires authorization from this account and the original author, with proper attribution. To care for your kidneys, begin by following the “Kidney Transplantation, Zhongshan Hospital, Fudan University” WeChat public account. You can also click [Read the Original] to explore Can Solid Organ Transplant Recipients Receive the COVID-19 Vaccine? A Comprehensive Explanation.
