Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

Hinterberger, Maria; Aichinger, Martin; Costa, Olivia Prazeres da; Voehringer, David; Hoffmann, Reinhard; Klein, Ludger

doi:10.1038/ni.1874

Cited by 219 publications

(261 citation statements)

References 54 publications

(59 reference statements)

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“…Nevertheless, it appears unlikely that distinct modalities of how TECs or other thymic APCs generate MHC IIbound epitopes are critical qualitative determinants of the ensuing fate of autoreactive CD4 T cells. Given that antigen presentation by mTECs can lead to both clonal deletion and T reg differentiation (Hinterberger et al, 2010), and considering the at least partial redundancy of TECs and DCs for T reg induction , we predict that for other combinations of TCR and/or self-antigen, T reginduction may also depend upon autophagy-mediated direct antigen presentation by TECs. However, future experimentation is needed to test this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Constructs containing a -globin intron followed by cDNAs encoding for GCL or GCL G120A , respectively, and a poly-A signal were inserted by homologous recombination into the mouse BAC RP23-77011 (BACPAC; Hinterberger et al, 2010). The targeting vectors contained homology boxes spanning nucleotides 379 to 2 (5) and 17 to 399 (3) of the Aire gene.…”

Section: Methodsmentioning

confidence: 99%

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Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

Aichinger¹,

Wu²,

Nedjic³

et al. 2013

J Cell Biol

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Macroautophagy serves cellular housekeeping and metabolic functions through delivery of cytoplasmic constituents for lysosomal degradation. In addition, it may mediate the unconventional presentation of intracellular antigens to CD4 + T cells; however, the physiological relevance of this endogenous MHC class II loading pathway remains poorly defined. Here, we characterize the role of macroautophagy in thymic epithelial cells (TECs) for negative selection. Direct presentation for clonal deletion of MHC class II-restricted thymocytes required macroautophagy for a mitochondrial version of a neo-antigen, but was autophagyindependent for a membrane-bound form. A model antigen specifically expressed in Aire + medullary TECs (mTECs) induced efficient deletion via direct presentation when targeted to autophagosomes, whereas interference with autophagosomal routing of this antigen through exchange of a single amino acid or ablation of an essential autophagy gene abolished direct presentation for negative selection. Furthermore, when this autophagy substrate was expressed by mTECs in high amounts, endogenous presentation and indirect presentation by DCs operated in a redundant manner, whereas macroautophagydependent endogenous loading was essential for clonal deletion at limiting antigen doses. Our findings suggest that macroautophagy supports central CD4 + T cell tolerance through facilitating the direct presentation of endogenous self-antigens by mTECs.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

Aichinger¹,

Wu²,

Nedjic³

et al. 2013

J Cell Biol

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“…Treg development in the thymus requires strong peptide-MHC interaction 39 and CD18 (ref. 40), and may share the same mTEC with CD4SP cells 41 . Mst1 − / − CD4SP cells exhibited decreased contact frequency and stable association with cognate Aire + ICAM-1 + mTEC.…”

Section: Discussionmentioning

confidence: 99%

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Ueda¹,

et al. 2012

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Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAm-1 within the medulla. using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire + ICAm-1 hi medullary thymic epithelia in a negatively selecting environment. notably, mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAm-1 results in inefficient migration and antigen recognition of CD4 + thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1 − / − mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. our results suggest that mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla.

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“…+ [36]. Le rôle de Aire a été également étudié dans la sélection négative des thymocytes CD8 + à l'aide de souris transgéniques OT-I qui possèdent des thymocytes CD8 + reconnaissant l'OVA dans le contexte des molécules de CMH I [35].…”

Section: Les Différents Rôles De Aire Dans L'induction De La Tolérancunclassified

Induction de la tolérance centrale dans le thymus par le facteur de transcription Aire

2015

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Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

Cited by 219 publications

References 54 publications

Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Induction de la tolérance centrale dans le thymus par le facteur de transcription Aire

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