Immune tolerance is a state in which the immune system does not mount a damaging response against a particular antigen, while retaining the capacity to respond to other antigens. Its principal physiological role is self-tolerance: preventing immune attack on the body’s own tissues. Tolerance depends on mechanisms that eliminate, inactivate, or restrain potentially harmful immune cells. It can also extend to foreign antigens under particular conditions, as demonstrated experimentally in tissue transplantation. (ncbi.nlm.nih.gov)
Biological basis and scope
The antigen receptors of adaptive immunity are generated through genetic rearrangements that produce a diverse repertoire. This diversity enables recognition of many potential threats but also generates T cells and B cells capable of recognizing self. Tolerance therefore involves both selection during lymphocyte development and continuing regulation after mature cells enter the circulation and tissues. Healthy individuals can retain self-reactive lymphocytes without developing autoimmune disease. (pmc.ncbi.nlm.nih.gov)
Tolerance is not simply an absence of immune activity. Antigen recognition can actively produce non-responsiveness rather than an effector response. A related condition, immunological ignorance, occurs when a potentially reactive lymphocyte does not encounter enough accessible antigen to become activated. This differs from mechanisms that directly alter or suppress the cell’s responsiveness. (ncbi.nlm.nih.gov)
Central tolerance
Central immune tolerance operates during lymphocyte development, principally in the thymus for T cells and the bone marrow for B cells. Its outcome depends on how developing cells recognize self-antigens and the signals accompanying that recognition. (pmc.ncbi.nlm.nih.gov)
Developing T cells recognize self-peptides presented by the major histocompatibility complex. Positive selection preserves cells capable of appropriately recognizing self-MHC molecules. Cells with strongly self-reactive receptors may instead undergo negative selection, including deletion through apoptosis. Some self-reactive developing cells differentiate into regulatory populations rather than conventional effector cells. These processes shape a useful but constrained T-cell repertoire. (pmc.ncbi.nlm.nih.gov)
Thymic epithelial cells express many antigens otherwise associated with particular peripheral tissues. The autoimmune regulator, AIRE, helps enable this expression, allowing developing T cells to encounter a broader representation of the body’s molecular components. Disruption of AIRE-dependent mechanisms is associated with impaired self-tolerance and autoimmune disease. (ncbi.nlm.nih.gov)
For immature B cells, a major mechanism is receptor editing: additional immunoglobulin gene rearrangements change the antigen receptor’s specificity. Self-reactive cells may also be deleted. Central tolerance is incomplete, making additional safeguards necessary outside the developmental organs. (ncbi.nlm.nih.gov)
Peripheral tolerance
Peripheral immune tolerance controls mature lymphocytes outside the thymus and bone marrow. It includes functional inactivation, deletion, and suppression by other cells. These mechanisms protect against self-reactive lymphocytes that escape developmental selection or encounter antigens mainly available in peripheral tissues. (ncbi.nlm.nih.gov)
Anergy is a state of reduced functional responsiveness following antigen recognition. In T cells, recognition without adequate co-stimulatory signals can lead to anergy or deletion rather than productive activation. Peripheral B-cell responses are likewise constrained by mechanisms including anergy and the absence of appropriate helper-T-cell interactions. This limits inappropriate antibody production against self. (ncbi.nlm.nih.gov)
Regulatory T cells provide active suppression of other immune cells. The transcription factor FOXP3 is central to the development and function of an important regulatory T-cell population. Mutations impairing FOXP3 function cause severe immune dysregulation, including the inherited condition IPEX syndrome, demonstrating the importance of this regulatory pathway. Regulatory T cells can arise in the thymus, while additional regulatory populations develop under peripheral conditions. (nobelprizemedicine.org)
Inhibitory immune checkpoints also restrain immune responses. Proteins such as CTLA-4 and PD-1 participate in pathways that reduce T-cell activity and help prevent damage to healthy tissues. (cancer.gov)
Physiological and clinical relevance
Loss of self-tolerance contributes to autoimmunity, but the presence of self-reactive cells alone does not establish disease. Their activation and regulation are also important. Rare inherited defects affecting AIRE or FOXP3 illustrate how disruption of particular tolerance mechanisms can produce immune-mediated tissue damage. (ncbi.nlm.nih.gov)
Tolerance also matters for interactions with harmless foreign material. Regulatory T cells and tolerogenic antigen-presenting cells participate in immune accommodation of commensal microorganisms. Research on allergy examines whether antigen-specific non-responsiveness can be established or maintained against otherwise harmful immune responses to environmental or food antigens. (nobelprize.org)
In organ transplantation, tolerance research seeks to control responses against donor antigens. Clinical studies investigate tolerance-inducing approaches alongside mechanistic measurements of immune responses. Conversely, in cancer, tumors can exploit inhibitory immune pathways. Checkpoint inhibitors block some of these signals to enhance antitumor responses, but can also cause immune-mediated inflammation in healthy organs. (niaid.nih.gov)
Historical development
Experiments by Peter Medawar and colleagues showed that exposure to cells from another mouse strain during embryonic development could permit later acceptance of grafts from that strain while preserving rejection of unrelated grafts. Frank Macfarlane Burnet and Medawar shared the 1960 Nobel Prize in Physiology or Medicine for the discovery of acquired immunological tolerance. (educationalgames.nobelprize.org)
The 2025 prize recognized Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for discoveries concerning peripheral immune tolerance, particularly regulatory T cells and the role of FOXP3. (nobelprize.org)