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Interferons (IFNs) are a family of proteins that are generated in response to viral infection and induce an antiviral response in many cell types. The COVID-19 pandemic revealed that patients with inborn errors of type-I IFN immunity were more prone to severe infections, but also found that many patients with severe COVID-19 had anti-IFN autoantibodies that led to acquired defects in type-I IFN immunity. These findings revealed the previously unappreciated finding that central immune tolerance to IFN is essential to immune health. Further evidence has also highlighted the importance of IFN within the thymus and its impact on T-cell development. This review will highlight what is known of IFN's role in T-cell development, T-cell central tolerance, and the impact of IFN on the thymus.

Section snippetsInterferon production in the thymus

T-cell central tolerance occurs within the thymus where developing thymocytes expressing newly generated T-cell receptors (TCRs) are selected for potential functionality and deleted if they possess high self-reactivity [1]. While Interferon (IFN) is primarily thought of as a proinflammatory cytokine produced transiently following pathogen exposure, recent evidence has revealed IFNs are continuously expressed in the thymus 2••, 3••. IFNs can be categorized into three families: type I, type II,

Interferon impact on T-cell selection

A growing body of work has demonstrated that thymic IFN has striking impacts on both thymocytes and antigen-presenting cells (APCs). IFNαR is broadly expressed by cells in the thymus, both on developing thymocytes and APCs (Figure 1). Meanwhile, IFNLR is restricted to thymic epithelial cells and select APCs, including B cells and thymic DC. In thymocytes, thymic type-I IFNs are involved in the late-stage maturation of single-positive (SP) thymocytes through cell-intrinsic effects of IFNαR

Interferonopathies and the thymus

The importance of regulating type-I IFN production and signaling can be appreciated in patients with inborn errors of type-I IFN and interferonopathies (disorders of dysregulated IFN production and signaling). Patients with inborn errors of type-I IFN are at risk for pathogen-mediated pathology [19], while patients with interferonopathies show a range of symptoms associated with autoinflammation that include skin and central nervous system (CNS) disease, lupus, and developmental delay [33].

Tonic interferon impact on T-cell reactivity

Type-I IFN is known to impact T-cell activation and differentiation during infection, but recent evidence has found that a subset of naive CD8SP, CD4SP, and Foxp3+ Treg cells express an IFN-stimulated gene signature at steady state 40, 41•, 42, 43, 44. It is not yet clear if this reflects IFN signaling in the thymus or the periphery or both (type-I and type-III IFNs are produced in intestinal sites at steady state 2••, 45). Nonetheless, the fact that IFN is impacting the transcriptome of the

Interferon and thymic atrophy

The thymus can be directly infected by a host of pathogens, including Mycobacterium tuberculosis, Toxoplasma gondii, HIV, and Lymphocytic choriomeningitis virus (LCMV) 48, 49, 50. Infection with these pathogens is associated with loss of thymic cellularity, also known as thymic atrophy [48]. Thymic atrophy has multiple causes but can be mediated by type-I IFNs 49, 50, 51•. However, this is associated with infection-derived IFNs, as those IFNs produced at steady state have not been associated

Conclusions

Thymic IFN plays crucial roles in the development of a healthy T-cell repertoire. IFN impacts thymocyte selection and maturation through T-cell-intrinsic signaling and extrinsically through activation of APC. Although some of the effects of steady-state thymic IFN have been elucidated, recent evidence suggests that the development and maturation of mTEC are required for immune tolerance to IFN. The same mechanisms that promote IFN production in mTEC are likely involved in the development of

Declaration of Competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We thank Maude Ashby for her helpful discussion and feedback on this review. This work was supported by the National Institutes of Health Grant P01 AI35296 and R37 AI39560 to KAH.

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