The antigen presentation pathway in medullary thymic epithelial cells, but not that in cortical thymic epithelial cells, conforms to the endocytic pathway

Kasai, Mari; Kominami, Eiki; Mizuochi, Toshiaki

doi:10.1002/(sici)1521-4141(199806)28:06<1867::aid-immu1867>3.0.co;2-k

Cited by 22 publications

(10 citation statements)

References 37 publications

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“…Peptide elution experiments utilizing purified B cells from DO-KO and DO-wild-type (DO-WT) mice were performed. We justified the use of B cells instead of mTECs for two main reasons: (1) the technical limitation of obtaining enough mTECS to attain reliable results and (2) the known similarities in expression of MHC class II molecules, DM, and cathepsins, the main components of the antigen processing machinery in mTECs [30][31][32][33][34][35], along with DO [8,36]. Analyses of two independent experiments (each comprising pools of 5 or 10 mice per group) showed that nearly 90% of eluted peptides were shared between the two strains, and 10% were unique peptides.…”

Section: Do-ko B Cells Present Peptides Of Lower Kinetic Stabilitymentioning

confidence: 99%

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

et al. 2020

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DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and wholebody imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development. Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.org/10.1371/journal.pbio.3000590 February 18, 2020 3 / 29Fig 2. Naïve DO-KO mice have an expanded CD4 T-cell compartment as well as increased expression of Tregs. (A) Breakdown of T-cell compartment in the spleens of naïve DO-WT (white) and DO-KO (red) mice. N = 8 mice per group. Data are represented as mean ± SEM. (B). Subdivision of the CD4 T-cell compartment showed that DO-KO mice have increased percentage of CD4 + CD25 + -expressing cells. N = 8 mice per group. Data are represented as mean ± SEM. (C). Naïve expression of the Foxp3 transcription factor in naïve CD4 + T cells from DO-WT (white) and DO-KO (red) mice. N = 21 mice per group. Experimental results depicted in this figure can be found in S2 Data. Data are represented as mean ± SEM. DO, HLA-DO; Foxp3, forkhead box P3; KO, knockout; Treg, regulatory T cell; WT, wild-type. https://doi.org/10.1371/journal.pbio.3000590.g002 Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.org/10.1371/journal.pbio.3000590 February 18, 2020 5 / 29 mice. (A) Representative curves showing the time course of disease development in DO-KO (red) and DO-WT mice (white). N = 5 mice per group, representative of >15 repeat experiments. Score system: 0 = no symptoms, 1 = limp tail, 2 = limp tail + partial hind limb paralysis, 3 = limp tail + total Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.EAE was induced as previously described in both DO-WT and DO-KO mice. Mice were humanely killed on Day 17 of disease, brains and spinal columns were pooled, and infiltrating Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.

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Section: Do-ko B Cells Present Peptides Of Lower Kinetic Stabilitymentioning

confidence: 99%

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

et al. 2020

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“…Both APCs and mTECs present exogenous antigens on MHC II via the endocytic pathway, although APCs are more efficient. For the presentation of intracellular peptides APCs, cTECs and mTECs use the constitutive secretory pathway and the lysosomal pathway via autophagy 49 , 50 . The role of autophagy in these selection processes during T‐cell maturation will be described here.…”

Section: Autophagy In Thymocyte Developmentmentioning

confidence: 99%

Autophagy in T‐cell development, activation and differentiation

2014

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Autophagy is a vital catabolic process for degrading bulky cytosolic contents, which cannot be resorbed via the proteasome. First described as a survival mechanism during nutrient starvation conditions, recent reports have demonstrated that autophagy supports metabolic functions of T cells at various stages of maturation and effector function. Autophagy is crucial for T-cell development at the precursor stage as self-renewability and quiescence of hematopoietic stem cells depend on autophagy of the mitochondria and the endoplasmic reticulum. Later, during development in the thymus, autophagy regulates peptide presentation in stromal cells and professional antigen-presenting cells, which mediate thymocyte selection. Furthermore, the metabolic changes when mature T cells enter the periphery and when they are activated are both dependent on autophagy. Lastly, autophagy prevents early aging and, thus, ensures maintenance of memory T cells. Autophagy is an eukaryotic, cytoplasmic (self-)recycling process, in which proteins as well as entire organelles are degraded via lysosomes. There are three different types of autophagy, namely chaperonemediated autophagy, microautophagy and macroautophagy. Chaperone-mediated autophagy, unlike the other two types of autophagy, only degrades soluble cytosolic proteins by directly transferring heat-shock cognate protein of 70 kDa-tagged proteins across the lysosomal membrane. 1 Both micro-and macroautophagy can be nonselective as well as specific in their cargo selection and both are capable of degrading large-sized molecules. During microautophagy, the lysosomal membrane invaginates to sequester cytosolic content directly. 2 Macroautophagy is distinct, in that a doublemembrane structure, the autophagosome, is formed around its cytosolic cargo. This is also the most well-studied type of autophagy, and as this review deals with macroautophagy, it will be referred to simply as 'autophagy' hereafter.Autophagy is essential for degradation of aggregated proteins (aggrephagy) 3 and damaged organelles including mitochondria (mitophagy), peroxisomes (pexophagy) and ER (ERphagy). These were previously reviewed in Ding and Yin, 4 Sakai et al. 5 and Bernales et al., 6 respectively. As autophagy is a fundamental process needed by almost all cell types to maintain cell homeostasis, a basal level of autophagy occurs constantly. 7 Beyond this, autophagy is vital for cells during stress conditions such as starvation, activation, growth and proliferation, to provide cells with essential metabolic intermediates. These basic autophagic functions are relevant in diseases as well as aging, as the accumulation of aggregated proteins, damaged organelles or other molecules is an underlying problem of many diseases. For instance, autophagy has been implicated in neurodegenerative diseases, 8,9 Crohn's disease, 10,11 cancer, 12,13 aging 4,15 and cystic fibrosis, 16 as well as metabolic-related diseases such as fatty liver (macrolipophagy), 17 autophagic vacuolar myopathies (glycogen degradation) 18,19 and di...

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“…Cathepsin S activity (B) and SDS-stable MHCII ab dimer level (C) were analyzed. Three independent experiments were performed, and the average enzyme activity and signal intensity are shown, with error bars indicating of Infectious Diseases) (Kasai et al, 1998 and. GM-CSFproducing CHO cells were from Dr. Sudo (Toray).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells

et al. 2005

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We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alphabeta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alphabeta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alphabeta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alphabeta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alphabeta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alphabeta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.

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The antigen presentation pathway in medullary thymic epithelial cells, but not that in cortical thymic epithelial cells, conforms to the endocytic pathway

Cited by 22 publications

References 37 publications

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

Autophagy in T‐cell development, activation and differentiation

IL-6-STAT3 Controls Intracellular MHC Class II αβ Dimer Level through Cathepsin S Activity in Dendritic Cells

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