Trends in Immunology
ReviewControl of central self-tolerance induction by autoreactive CD4+ thymocytes
Section snippets
Function of medullary thymic epithelial cells
The thymus comprises a series of specialized microenvironments that support the homing, survival, proliferation, differentiation, migration and selection of developing thymocytes 1, 2. These processes culminate in the emergence of a mature T-cell population that carries a randomly generated T-cell-receptor (TCR) repertoire that has been selected for its functional utility, and purged of autoreactive specificities. Thymocyte development and selection are guided by the thymic stroma, a key
Terminal differentiation model of mTEC development
cTECs and mTECs differentiate from bipotent TEC progenitors (bTECps) present in the embryonic and postnatal thymus 19, 20 (Figure 1). The subsequent differentiation of bTECps into mTECs has been proposed to occur via committed mTEC progenitors (mTECps) [21] (Figure 1). The unambiguous identification of bTECps and mTECps has been hampered by the scarcity of reliable markers. In contrast, major progress has been made in our ability to use well-defined markers to identify and study the
Control of mTEC development by NF-κB activation
The analysis of a growing number of mutant mice has established that intracellular signaling pathways leading to the activation of transcription factors belonging to the nuclear factor kappa B (NF-κB) family are of central importance for the generation of a correctly organized and functional medulla (Table 1). NF-κB factors can be activated by two signal-transduction pathways, referred to as the canonical (classical) and noncanonical (alternative or nonclassical) pathways (Figure 2) [25]. Both
TNF superfamily receptors and ligands governing mTEC development
Members of the tumor necrosis factor (TNF) superfamily of receptors (TNFSFRs) and their corresponding TNF superfamily ligands (TNFSFLs) regulate various processes in the immune system, including lymphoid tissue organogenesis [37]. TNFSFRs typically signal via the canonical, the noncanonical or both NF-κB pathways [36]. mTECs express a diverse set of different TNFSFRs [38]. Recent work has established that at least three of these – lymphotoxin β receptor (LTβR), receptor activator of NF-κB
Cellular interactions driving mTEC development
The formation of cortical and medullary compartments in the postnatal thymus is dependent on bidirectional communication between developing thymocytes and TECs, a process referred to as ‘thymic crosstalk’ [51]. TCRα−/− and ZAP70−/− mice, which exhibit a block in thymocyte differentiation at the DP stage, contain only scattered and small clusters of mTECs 52, 53, 54. Reconstitution of T-cell-deficient severe combined immunodeficient (SCID) mice with mature T cells or TCR-bearing thymocytes was
Autoreactive CD4+ thymocytes control mature-mTEC cellularity
CD40L and RANKL are primarily membrane-bound ligands. Although soluble RANKL can be shed from the cell surface by proteolytic cleavage, membrane-bound RANKL was shown to sustain osteoclast generation more efficiently than did soluble RANKL 62, 63. These considerations suggested that CD40L and RANKL signals delivered to mTECs by CD4+ thymocytes are likely to be provided in the context of physical interactions between the two cell types. This suggestion was confirmed by a series of experiments
Concluding remarks
Through their unique property of activating an extensive PGE program, mature mTECs constitute a major source of peripheral TRAs towards which negative selection of autoreactive T cells is induced in the thymus. Given this pivotal role in driving negative selection, unraveling the processes that control the development and function of mature mTECs is crucial for our comprehension of the establishment of central T-cell tolerance in health and its breakdown as a cause of autoimmune diseases.
Acknowledgements
Work in the laboratory of W. Reith was supported by the Swiss National Science Foundation (grant 3100A0-105895), Geneva Cancer League, Swiss Multiple Sclerosis Society and National Center of Competence in Research NCCR-NEURO. Work in the laboratory of G. Holländer was supported by the Swiss National Science Foundation (grant 3100-68310.02), National Institutes of Health (grant R01-AI057477-01) and European Community Integrated Project Euro-Thymaide. M. Irla was supported by fellowships from
Glossary
- Autoimmune regulator (Aire)
- a transcription factor that activates the expression in mTECs of thousands of genes that are normally expressed in a tissue-restricted manner in peripheral tissues.
- Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or autoimmune polyendocrinopathy syndrome 1 (APS1)
- a rare autoimmune disease caused by mutations in the gene encoding Aire; the disease is characterized by a diverse array of clinical features, particularly failure in the functions of
References (65)
- et al.
The two NF-kappaB activation pathways and their role in innate and adaptive immunity
Trends Immunol.
(2004) NF-κB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells
J. Biol. Chem.
(2006)Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κ B/Rel family
Cell
(1995)The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance
Immunity
(2008)- et al.
Crosstalk via the NF-κB signaling system
Cytokine Growth Factor Rev.
(2008) The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator
Immunity
(2008)Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity
Immunity
(2008)Crosstalk in the mouse thymus
Immunol. Today
(1994)Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells
Blood
(2003)Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-κB ligand: modulation of the expression by osteotropic factors and cytokines
Biochem. Biophys. Res. Commun.
(2000)
Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-κB ligand
J. Biol. Chem.
Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells
Blood
Journey through the thymus: stromal guides for T-cell development and selection
Nat. Rev. Immunol.
Zoned out: functional mapping of stromal signaling microenvironments in the thymus
Annu. Rev. Immunol.
CCR7 signals are essential for cortex-medulla migration of developing thymocytes
J. Exp. Med.
CCR7 directs the migration of thymocytes into the thymic medulla
J. Immunol.
Lymphostromal interactions in thymic development and function
Nat. Rev. Immunol.
Central tolerance: learning self-control in the thymus
Nat. Rev. Immunol.
NIK-dependent RelB activation defines a unique signaling pathway for the development of V alpha 14i NKT cells
J. Exp. Med.
Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development
J. Exp. Med.
Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development
Proc. Natl. Acad. Sci. U. S. A.
Dendritic cells in the thymus contribute to T-regulatory cell induction
Proc. Natl. Acad. Sci. U. S. A.
Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells
Nat. Immunol.
A central role for central tolerance
Annu. Rev. Immunol.
Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation
J. Exp. Med.
The thymic medulla: a unique microenvironment for intercellular self-antigen transfer
J. Exp. Med.
Projection of an immunological self shadow within the thymus by the aire protein
Science
A decade of AIRE
Nat. Rev. Immunol.
Spontaneous autoimmunity prevented by thymic expression of a single self-antigen
J. Exp. Med.
Thymus-specific deletion of insulin induces autoimmune diabetes
EMBO J.
Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium
Nature
Formation of a functional thymus initiated by a postnatal epithelial progenitor cell
Nature
Cited by (53)
A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice
2017, BloodCitation Excerpt :Medullary TECs (mTECs) are essential for negative selection and regulatory T (Treg) cell development, in part because of their expression of the autoimmune regulator (AIRE).2 Numerous studies have revealed that defects in TEC differentiation can, in turn, perturb T-cell differentiation to cause immunodeficiency or autoimmune disease.3 Given the importance of TECs for acquired immunity, the molecular mechanisms that govern their generation and function have been a major focus in the field, with a view to developing strategies to improve or restore thymic function in immunocompromised patients.4,5
Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice
2017, BloodCitation Excerpt :These results are consistent with previous studies coupling p53 induction to the NFκB pathway,29 which is in turn engaged by mTEC-inducing TNFRSF signaling.19 Yet the reduction in mTECs of p53cKO mice was not as severe as that reported in RANK-deficient mice.19 The differentiation of mTECs depends on the coordinated action of RANK, CD40, and LTβR signaling.1
Multiple Sclerosis in Women: Vitamin D and Estrogen Synergy for Autoimmune T-Cell Regulation and Demyelinating Disease Prevention
2017, Nutrition and Lifestyle in Neurological Autoimmune Diseases: Multiple SclerosisTNF superfamily members play distinct roles in shaping the thymic stromal microenvironment
2016, Molecular ImmunologyCitation Excerpt :Finally, mice deficient for TNFα, which is structurally similar to LTα and LTβ proteins, exhibit a normal thymic stromal architecture (Grech et al., 2000). Because the majority of information on thymic signaling has been gained using KO mouse models of different TNFSF members that often result in the developmental block in mTECs (Irla et al., 2010), it has been difficult to differentiate between direct and indirect transcriptional effects of these signals. To study the effects of isolated signals on the thymic stroma, we conducted a gene expression profiling analysis to characterize the effects of RANKL, TNFα, CD40L, LIGHT and LTβR signaling using a fetal thymus organ culture (FTOC) system.
For3D: Full organ reconstruction in 3D, an automatized tool for deciphering the complexity of lymphoid organs
2015, Journal of Immunological Methods