Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

Klein, Ludger; Hinterberger, Maria; Rohrscheidt, Julia von; Aichinger, Martin

doi:10.1016/j.it.2011.03.002

Cited by 51 publications

(37 citation statements)

References 49 publications

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“…Vice versa, proteins or peptides can shuttle out of the lysosome into the cytosol and thus gain access to the MHC I pathway 22 . In addition to this intracellular cross-talk, DCs may take up antigens from other cells such as mTECs, further broadening their peptide repertoire 25,26 .…”

Section: Resultsmentioning

confidence: 99%

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

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Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant crosstalk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune-and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.

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Section: Resultsmentioning

confidence: 99%

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

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“…There is convincing evidence that both a direct pathway (Oukka et al, 1996;Klein et al, 1998;Aschenbrenner et al, 2007;Hinterberger et al, 2010;Hubert et al, 2011) and an indirect pathway via DCs (Gallegos and Bevan, 2004;Koble and Kyewski, 2009;Hubert et al, 2011) can operate in this context. The parameters governing the requirement for one or the other mechanism remain to be established (Klein et al, 2011). We suggest that membrane associated self-antigens as well as substrates of autophagy (as for instance specified by partitioning of the respective antigen into particular organelles such as mitochondria or the nucleus) may preferentially be presented via the direct pathway.…”

Section: Discussionmentioning

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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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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“…Lors de leur différenciation dans le thymus, les cellules T dont le TCR (T cell receptor) réagit avec les antigènes Figure 1B) (➜). Ces Ag exprimés par les mTEC sont soit directement présentés par les mTEC, soit cross-présentés par les cellules dendritiques aux thymocytes SP [2]. La médulla constitue donc un microenvironnement spécialisé dans l'élimina-tion des cellules T autoréactives via une collaboration étroite entre les mTEC et les cellules dendritiques.…”

Section: Resultsunclassified

Cellules épithéliales médullaires thymiques exprimant Aire

Irla

2012

Med Sci (Paris)

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Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

Cited by 51 publications

References 49 publications

Exploring the MHC-peptide matrix of central tolerance in the human thymus

Exploring the MHC-peptide matrix of central tolerance in the human thymus

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

Cellules épithéliales médullaires thymiques exprimant Aire

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