What is immune tolerance ?

Immune tolerance is a crucial physiological process that enables the immune system to distinguish between harmful pathogens and the body’s own tissues. This mechanism is essential for preventing autoimmune diseases, where the immune system mistakenly attacks healthy cells.

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AMPK substrates act in specific subcellular locales to rewire metabolism.

The mechanism of T cell tolerance. Central tolerance of T cells occurs in the thymus. Hematopoietic lymphoid progenitors migrate to cortex, where they are screened by thymic epithelia cells and develop into CD4+CD8+ double-positive (DP) thymocytes expressing the T-cell antigen receptor (TCR). DP cells migrate to the medulla. After screening for the ability to bind to self-peptide-associated major histocompatibility complex class I (MHC-I) or MHC class II (MHC-II) molecules on the antigen-presenting cell (APC) surface, DP cells develop into CD4+CD8+ DP thymocytes expressing the TCR. Screening for binding capacity of molecules culminating in Treg CD8+ T cells, and CD4+ T cells migrate to lymph node to undergo peripheral tolerance.

Peripheral tolerance mechanisms, such as exhaustion, deletion, anergy, and regulation are mainly relied upon to suppress the activity of self-reactive T cells. Exhaustion and deletion are realized through inhibiting cell function or proliferative capacity of effector T cell and apoptosis. Anergy describes a state of hyporesponsiveness of naive T cells to TCR stimuli after exposure to antigen. Treg cells regulate by inhibiting effector T cell activity and B cell proliferation via interleukin-(IL)-10, Transforming growth factor-β (TGF-beta), and IL-35.

Key mechanisms

Central Tolerance: Occurs during the development of immune cells in the thymus (for T cells) and bone marrow (for B cells). Autoreactive lymphocytes are eliminated through a process called negative selection, ensuring that only non-reactive cells enter circulation.
Peripheral Tolerance: This mechanism acts on autoreactive cells that escape central tolerance. It involves processes like anergy (functional inactivation) and deletion of these cells, preventing them from causing harm.

Anergy refers to the state in which T cells become functionally inactive upon encountering self-antigens without the necessary costimulatory signals

The role of Tregs in immune tolerance

Regulatory T cells (Tregs), particularly those expressing the transcription factor FOXP3, play a pivotal role in maintaining immunological tolerance and preventing autoimmunity. These cells are essential for distinguishing between self and non-self antigens, thereby regulating immune responses to avoid harmful reactions against the body’s own tissues.

Tregs produce several immunosuppressive cytokines, including IL-10, TGF-β, and IL-35, which inhibit the activation and proliferation of effector T cells (Teff) and other immune cells. This cytokine secretion helps create an environment conducive to immunological tolerance and limits inflammatory responses.

Importance in autoimmunity and diseases

THe proper functioning of Tregs is critical for preventing autoimmune diseases. A deficiency or dysfunction in Tregs can lead to a breakdown of self-tolerance, resulting in conditions such as rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Studies have shown that individuals with autoimmune diseases often exhibit reduced numbers or impaired function of Tregs, highlighting their protective role in immune regulation.

Therapeutics approaches to enhance immune tolerance

Recent advancements in immunotherapy aim to restore or enhance immune tolerance through various strategies:

Tolerogenic Vaccines: Designed to induce specific immune tolerance by presenting autoantigens to the immune system, thus reducing harmful responses.
Adoptive Cell Therapies: Utilizing regulatory T cells (Tregs) to suppress autoreactive immune responses.
Biomaterials for Targeted Delivery: Innovative biomaterial strategies are being developed to selectively induce antigen-specific tolerance without broad immunosuppression. These materials can control the delivery of tolerogenic signals directly to immune tissues.

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Immune tolerance biomarker list

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Human signaling pathway

Signaling Pathways	Product ref	Informations
Immune Tolerance	IT1H1	Download biomarker list

Species : Mus musculus (mouse)

Mouse signaling pathway

Signaling Pathways	Product ref	Informations
Immune Tolerance	IT1M1	Download biomarker list

Species : Rattus norvegicus (rat)

Rat signaling pathway

Signaling Pathways	Product ref	Informations
Immune Tolerance	*******	Biomarker list in progress.

Species : Sus Scrofa (Pig)

Pig Immune Tolerance

Signaling Pathways	Product ref	Informations
Immune Tolerance	*******	Biomarker list in progress.

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Bibliography

1. Kenison JE, et al. Therapeutic induction of antigen-specific immune tolerance. Nat Rev Immunol. (2024);24(5):338-357.

2. eng X, et al. Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells. Asia Pac Allergy. (2023)8;13(4):175–186..

3. Cifuentes-Rius A, et al . Inducing immune tolerance with dendritic cell-targeting nanomedicines. Nat Nanotechnol. (2021);16(1):37-46.

4. Moorman CD, et al . Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 Therapy. Front Immunol. (2021)29:12:657768.

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