The immune system must simultaneously protect the body against infections while avoiding attacks on self-tissues. This is achieved through central immune tolerance, which develops in the thymus, where developing T cells are tested for their ability to recognize—but not attack—self-antigens. Cells capable of causing autoimmune reactions are either eliminated or differentiated into regulatory T cells (Tregs) that suppress excessive immune responses.
For many years, medullary thymic epithelial cells (mTECs) were considered the principal mediators of this process. These cells can synthesize thousands of self-antigens, including tissue-specific antigens that are normally expressed only in individual organs. The key regulator of this process is the AIRE protein, which drives tissue-specific antigen expression in mTECs, allowing developing T cells to encounter antigens from virtually every tissue in the body. AIRE deficiency disrupts this process and results in severe autoimmune disease.
Recent studies have shown that a much more complex system generates immune tolerance. The thymus contains several mTEC populations that resemble cells from various peripheral tissues, including the skin, intestine, respiratory tract, muscles, and other organs. These cells are known as mimetic cells because they reproduce the characteristics of their peripheral counterparts.
Mimetic cells express tissue-specific antigens independently of AIRE. Instead, their differentiation is controlled by transcription factors responsible for the development of the corresponding tissue-specific cell types. Most mimetic cell populations continue to develop even in the absence of AIRE, indicating the existence of an independent mechanism of immune tolerance.
Mimetic cells protect against autoimmunity. When a particular antigen is expressed by these cells, the immune system no longer recognizes it as foreign. Conversely, the absence of specific mimetic cell populations leads to the production of autoantibodies against the thyroid gland, stomach, and other organs.
The functions of mimetic cells extend beyond self-antigen presentation. Some produce signaling molecules that regulate immune responses, contribute to thymic involution, and influence B-cell development.
Among these signaling molecules are thymic interferons (IFNs). Thymic IFNs play a dual role: they serve as self-antigens and regulate the development of antigen-presenting cells and thymocytes.
Thymic Interferons Are Produced Even in the Absence of Infection
Type I and type III interferons are typically produced in response to infection, inducing the expression of interferon-stimulated genes (ISGs) that perform three key functions:
- Establish an antimicrobial state in infected and neighboring cells to limit pathogen spread.
- Regulate immune responses by promoting antigen presentation and activation of innate immune cells.
- Activate adaptive immunity by supporting T-cell effector responses and immunological memory.
However, interferons are produced in the thymus even in the absence of infection. Mouse studies demonstrated that IFN-β and IFN-λ are constitutively expressed exclusively by mature mTECs under steady-state conditions. Their production depends on AIRE and is virtually absent from other thymic cell types.
Production of thymic IFNs begins early in development, peaks approximately three weeks after birth, and then persists at low levels throughout adulthood. This process is independent of the microbiota, infection, or activation of innate immune receptors.
Thymic Interferons Are Required for Antigen-Presenting Cell Maturation
Type I and type III interferons regulate the function of thymic cells. They activate ISGs in epithelial cells, B cells, dendritic cells, and certain macrophages, although the magnitude and nature of the response differ among cell populations.
Their most pronounced effects are observed in antigen-presenting cells. Type III interferons are required for:
- Survival, proliferation, and activation of thymic B cells.
- Maturation of the DC1 dendritic cell subset, whereas DC2 maturation is independent of IFN-III.
- Maintenance of a distinct population of thymic macrophages.
Thymic Interferons Prevent Autoimmune Responses
Type I and type III interferons in the thymus perform a dual function. In addition to regulating antigen-presenting cell maturation, they contribute to immune tolerance by acting as self-antigens. They also induce ISG expression, expanding the repertoire of self-antigens encountered by developing T cells.
Interferons as Self-Antigens. The presence of autoantibodies against type I interferons is associated with severe autoimmune disorders. Autoantibodies against IFN-I have also been reported in conditions involving defective thymic selection. Furthermore, neutralizing autoantibodies against IFN-I have been detected in approximately 4% of uninfected individuals aged 70 years or older. These observations suggest that declining thymic function may contribute to autoimmune diseases involving IFN-I.
Effects of Interferons on T-Cell Selection. Mouse studies showed that disruption of IFN-III signaling reduced regulatory T-cell generation, impaired the deletion of potentially self-reactive T cells, and led to autoimmune responses. Inflammatory infiltrates and increased frequencies of tissue-specific autoantibodies accompanied these effects. Importantly, type I and type III interferons did not affect the overall number of thymocytes or the expression of functional T-cell markers.
Impaired interferon signaling also reduced regulatory T cell diversity. The most pronounced defects occurred when both type I and type III interferon signaling pathways were disrupted simultaneously, disrupting the balance between the deletion of self-reactive T cells and the generation of regulatory T cells. In the absence of IFN-I signaling, potentially self-reactive T cells may escape the thymus, enter peripheral tissues, and become activated during inflammation, thereby triggering autoimmune responses.
The Thymus as a Site of Sterile Inflammation
The thymus contains constitutively activated antigen-presenting cells that reproduce key features of inflammatory responses and present inflammation-associated self-antigens to developing T cells. This enables immune tolerance to these antigens to be established before T cells encounter them in peripheral tissues. If T cells are not fully tolerant to inflammation-associated self-antigens, repeated inflammatory responses throughout life may initiate and amplify autoimmune disease.
Even in the absence of infection, TLR signaling pathways and type II cytokines (IL-4, IL-5, and IL-13) remain constitutively active in the thymus. These pathways regulate the maturation of antigen-presenting cells, the development of regulatory T cells, and the deletion of self-reactive T cells.
Conclusion
Immune tolerance is established through multiple complementary mechanisms. In addition to AIRE-dependent expression of tissue-specific antigens in the thymus, mimetic cells play a critical role by expressing tissue-specific antigens independently of AIRE.
Type I and type III interferons produced by AIRE-positive mTECs are essential for antigen-presenting cell maturation and the establishment of the T-cell repertoire. Disruption of interferon signaling reduces regulatory T-cell numbers and impairs the elimination of self-reactive T cells, highlighting the central role of interferons in maintaining immune tolerance.
The thymus establishes tolerance not only to tissue-specific antigens but also to inflammation-associated self-antigens. This system may help prevent activation of self-reactive T cells during infections and other inflammatory conditions.
Reference
Thymic interferons: a little goes a long way
