Project description:Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8αα+MHC-II+ cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue to terminate an on-going autoimmune inflammation by selective killing of effector autoreactive T cells. Now, we showed that this cell used a cytotoxic machinery of Ly49s+ NK cells in killing of target T cells. Thus, this CD8αα+MHC-II+ cell, which previously was thought a professional APC, is an antigen presenting-NK (AP-NK) cell. Following its coupling with target T cells through antigen presentation, killing stimulatory receptor Ly49s6 and co-receptor CD8αα on this cell used non-classic MHC-I RT1CE16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of RT1CE16 were highly susceptible to the killing by the CD8αα+ AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity, and thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, CD8αα+ AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNM-NM-3. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNM-NM-3 treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNM-NM-3 acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity. TC-1/A9 cultured cells treated with IFN gama or nothing. 3 biological replicates per condition.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNM-NM-3. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNM-NM-3 treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNM-NM-3 acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity. TC-1/A9 cultured cells treated with DAC/TSA or nothing. 3 biological replicates per condition.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNM-NM-3. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNM-NM-3 treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNM-NM-3 acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity. RVP3 cultured cells treated with DAC/TSA or nothing. 3 biological replicates per condition.
Project description:The TCRαβ CD8αα+ intraepithelial lymphocytes (IELs) play a significant role in primary immune defence in the small intestine. The canonical model of their development distinguishes TCRαβ IELs into induced and natural (TCRαβ CD8αα+) types, each influenced by distinct developmental pathways and antigen encounters. It is believed that natural CD8αα+ IELs differentiate solely from triple positive (TP) CD4+CD8αβ+CD8αα+ thymic progenitors that recognized self MHC-peptide complexes with high affinity but avoided deletion during selection. Our investigation reveals that, in addition to this central commitment, the CD8αα+ IELs undergo in situ enrichment through recruitment from peripheral CD4+ and CD8αβ+ T cell populations. We found that the functional makeup of individual clones within the CD8αα+ IEL subset is dictated by their origin. We demonstrate that expression of Bmp7 or Ly49 (Ly49C, F, H, and I) serve as markers indicating the CD8αα+ IELs’ peripheral provenance: CD8αβ+ and CD4+ T lymphocytes, respectively.
Project description:The TCRαβ CD8αα+ intraepithelial lymphocytes (IELs) play a significant role in primary immune defence in the small intestine. The canonical model of their development distinguishes TCRαβ IELs into induced and natural (TCRαβ CD8αα+) types, each influenced by distinct developmental pathways and antigen encounters. It is believed that natural CD8αα+ IELs differentiate solely from triple positive (TP) CD4+CD8αβ+CD8αα+ thymic progenitors that recognized self MHC-peptide complexes with high affinity but avoided deletion during selection. Our investigation reveals that, in addition to this central commitment, the CD8αα+ IELs undergo in situ enrichment through recruitment from peripheral CD4+ and CD8αβ+ T cell populations. We found that the functional makeup of individual clones within the CD8αα+ IEL subset is dictated by their origin. We demonstrate that expression of Bmp7 or Ly49 (Ly49C, F, H, and I) serve as markers indicating the CD8αα+ IELs’ peripheral provenance: CD8αβ+ and CD4+ T lymphocytes, respectively.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNγ. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNγ acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNγ. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNγ acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity.
Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNγ. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNγ acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity.
Project description:Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. LAG-3, an inhibitory receptor specifically expressed on activated T cells, binds to MHC-II as its canonical ligand. Using artificial antigen-presenting-cells reconstituting cognate or non-cognate peptide-MHC-II, we discovered that MHC-II interaction alone is insufficient for LAG-3's function. Instead, LAG-3's proximity to TCR but not CD4 coreceptor, facilitated by cognate peptide-MHC-II, is crucial in mediating T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif and disrupts CD3ε/Lck association. To enhance LAG-3's proximity to TCR complex, an Fc-attenuated LAG-3/TCR bispecific antibody was generated, transforming LAG-3 antagonists into LAG-3-dependent potent suppressors of both CD4 and CD8 T cells, and alleviating autoimmune symptoms in mouse models. Our findings reveal a unique checkpoint cis-modulatory mechanism and provide potential strategies, distinct from PD-1 agonists and others, for T cell-driven autoimmune diseases that lack effective and well-tolerated immunotherapies.
