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Immune Tolerance: What Is Immune Tolerance & Types of Immunological Tolerance

Updated on Nov 28, 2023


Ah, the wonders of the human immune system. It is undeniably powerful, protecting the body from a wide range of pathogens. At the same time, it must also avoid harming the body through excessive inflammatory reactions to non-pathogenic materials.

The immune system can recognize which molecules are produced by the body and which are not. It can then attack foreign invaders while avoiding self-produced antigens. When functioning properly, this process prevents misguided immune responses to non-harmful antigens; but if something goes wrong, it can lead to disorders like allergies or autoimmune diseases.

What Is Tolerance in Immunology?

Immune tolerance, or immunological tolerance, is the process by which immune cells are made unresponsive to self-antigens to prevent damage to healthy tissues.  It prevents an immune response to antigens produced by the body itself or recognized from a prior encounter. Tolerance is built by the body’s ability to determine self vs. non-self cells.

Regulatory T Cells for Immune Tolerance

Immune cell functionality—via essential antigen-recognizing abilities—is integral to peripheral immune tolerance. One subtype of T cells called regulatory T cells, or Treg cells, are indispensable to this process. 

Treg cells are created during the immune system’s normal selection process in the thymus. They maintain immune tolerance by distinguishing self-antigens from foreign antigens and finding overactive effector cells that evade other mechanisms of negative selection. Treg cells will also suppress or halt an inflammatory reaction once it becomes detrimental to the body. 

There are two types of immune tolerance: self-tolerance and induced tolerance and both play an integral role in defending the body from harmful inflammation. 


The immune system can identify and not react against self-produced antigens, which is known as self-tolerance. Autoimmune disease may occur if this ability is lost and the body begins to attack its cells.

Throughout an individual’s life, there is an ongoing active process of immune tolerance to self. Autoreactive lymphocytes are eliminated during development, and regulatory T cells help to keep them in check during circulation.

Possible Causes for a Lack of Self-Tolerance

The loss of self-tolerance is the primary driver of autoimmune diseases. Self-tolerance and autoimmunity can have numerous causes. 

The mechanism that controls tolerance involves deleting overactive and autoreactive cells during negative selection processes in the thymus before naive T cells mature. This process screens naive T cells for reactivity to self-elements. Naive T cells that show naive cell activation to self-antigens during development are negatively selected and apoptosis is induced. 

This mechanism can be manipulated based on the concentrations of negative selection control and cell surface receptors, such as Fas and FasLigand, which regulate cellular apoptosis. T cell suppression is mediated by cytokines, and some foreign particles and pathogens can modify the abilities, structure, and number of cytokines circulating. 

Risks of Losing Self-Tolerance

A decrease in self-tolerance can cause various autoimmune diseases. The immune system’s ability to distinguish pathogens from self-antigens is critical to the functionality of its infection protections. When the immune system fails to tolerate self-cells, the body will go into an autoimmune state, attacking self-tissues, leading to illness and, in some cases, death. 

Induced Tolerance

Induced tolerance occurs when the immune system actively avoids responding to an external antigen. Previous encounters with that antigen induce this immunological tolerance. An example of induced tolerance is a deliberate manipulation of the immune system to avoid the rejection of transplanted organs or to provide protection from allergic reactions.

Practical Applications of Inducing Tolerance

Current practices in transplantation medicine immune tolerance mechanisms to good advantage by manipulating the immune system to tolerate transplanted organs and tissues through immunosuppressive drugs. Inflammation and immune reactions to transplanted cells are common complications of major organ transplants. By exploiting the body’s natural self-tolerance processes, a transplant patient is better protected against rejection of the transplanted cellular material. 

In addition to transplant medicine, induction of immune tolerance is done regularly in the treatment of allergies. Antigen immunotherapy introduces very low doses of the antigen (below the activation threshold of the immune cells) either by injection or sublingually to retrain the immune system to a tolerant state. 

Central Tolerance vs. Peripheral Tolerance: What’s the Difference?

Immune tolerance mechanisms are separated into two categories: central tolerance and peripheral tolerance. These mechanisms occur at different stages of the lymphocyte life cycle, and a deficiency in either category can result in serious consequences to the body.

Central Tolerance

Central tolerance mechanisms occur during lymphocyte development, either in the thymus for T cells or in the bone marrow for B cells. Through this process, immune cells with T cell receptors (TCRs) or B cell receptors (BCRs) that can recognize and bind to self-antigens are eliminated—or, for some T cells, differentiated into Tregs. By preventing the maturation of autoreactive lymphocytes, central tolerance helps the immune system discriminate between self-antigens and foreign materials.

Elimination of self-reactive lymphocytes can occur by one of several immune tolerance mechanisms:

  • Deletion: Cell death is induced in autoreactive immune cells.
  • Anergy: Autoreactive immune cells receive signals that cause their antigen simulation to cease, leaving them functionally incapable of differentiating into effector cells.
  • Ignorance: Autoreactive immune cells that either do not encounter their self-antigen or bind to their self-antigen so weakly that they are “ignorant” of their reaction, do not differentiate into effector cells.

Some autoreactive lymphocytes, however, are not eliminated or differentiated into Tregs during development. For these cells—or for ignorant lymphocytes that encounter their self-antigen later—there are additional immune tolerance mechanisms in place.

Examples of Central Tolerance

Central tolerance processes take place during immune cell development, modifying the number of naive lymphocytes circulating the periphery. Central tolerance— referring to the location of these processes—occurs in the central lymphoid organs, the bone marrow, and the thymus. When autoreactive T cells are deleted for binding to self-antigens in the thymus, central tolerance properly enacts immune cell regulation. 

Peripheral Tolerance

After mature lymphocytes are released into the lymph nodes or other tissues, peripheral tolerance mechanisms occur to prevent autoreactive immune cells from causing damage in the periphery. Tregs are one mechanism of peripheral tolerance that induces suppression or anergy of autoreactive cells that have escaped other mechanisms of central tolerance, preventing the immune system from overreacting to self- or other non-harmful antigens.

Examples of Peripheral Tolerance

The regulation of the inflammatory response in the peripheral lymphoid organs occurs during regular immune cell circulation. These organs include secondary lymphoid organs such as the mucosal membranes and lymph nodes. Peripheral tolerance enacts the second stage of immune tolerance, safeguarding the body from harmful inflammation when autoreactive cells escape central tolerance selection and reach the periphery.

Anergy is a type of peripheral tolerance that occurs when a cell is activated without the necessary costimulation and histocompatibility complex. Although anergic cells remain alive and reversible, they are unable to respond to antigenic activation.

Another crucial aspect of peripheral tolerance is the involvement of Treg cells, cells differentiated by exposure to specific cytokines, which help regulate overactive T cells.

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