Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity
J Immunol. 2024 Apr 12:ji2300290. doi: 10.4049/jimmunol.2300290. Online ahead of print.ABSTRACTPlasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and β3-knockout pDCs produce more IFN-I and inflammatory cytokines tha...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Alina K Lorant Anna E Yoshida Emily A Gilbertson Talyn Chu Caroline Stefani Mridu Acharya Jessica A Hamerman Adam Lacy-Hulbert Source Type: research
Disruption of IFN γ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells
In this study, we further investigated the importance of IFNγ-, GZMB-, PRF1-, and LYST-associated pathways in CD8+ T cell-mediated suppression. Using the CRISPR-Cas9 ribonucleoprotein transfection system, we first optimized efficient gene knockout while maintaining high viability in primary bulk human CD8+ T cells. Knockout was confirmed through quantitative real-time PCR assays in all cases, combined with flow cytometry where appropriate, as well as confirmation of insertions and/or deletions at genomic target sites. We observed that the knockout of IFNγ, GZMB, PRF1, or LYST, but not the knockout of IL4 or IL5, resulted...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Chakrapani Vemulawada Pranav S Renavikar Michael P Crawford Scott Steward-Tharp Nitin J Karandikar Source Type: research
Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity
J Immunol. 2024 Apr 12:ji2300290. doi: 10.4049/jimmunol.2300290. Online ahead of print.ABSTRACTPlasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and β3-knockout pDCs produce more IFN-I and inflammatory cytokines tha...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Alina K Lorant Anna E Yoshida Emily A Gilbertson Talyn Chu Caroline Stefani Mridu Acharya Jessica A Hamerman Adam Lacy-Hulbert Source Type: research
Disruption of IFN γ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells
In this study, we further investigated the importance of IFNγ-, GZMB-, PRF1-, and LYST-associated pathways in CD8+ T cell-mediated suppression. Using the CRISPR-Cas9 ribonucleoprotein transfection system, we first optimized efficient gene knockout while maintaining high viability in primary bulk human CD8+ T cells. Knockout was confirmed through quantitative real-time PCR assays in all cases, combined with flow cytometry where appropriate, as well as confirmation of insertions and/or deletions at genomic target sites. We observed that the knockout of IFNγ, GZMB, PRF1, or LYST, but not the knockout of IL4 or IL5, resulted...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Chakrapani Vemulawada Pranav S Renavikar Michael P Crawford Scott Steward-Tharp Nitin J Karandikar Source Type: research
Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity
J Immunol. 2024 Apr 12:ji2300290. doi: 10.4049/jimmunol.2300290. Online ahead of print.ABSTRACTPlasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models. We show that αv and β3-knockout pDCs produce more IFN-I and inflammatory cytokines tha...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Alina K Lorant Anna E Yoshida Emily A Gilbertson Talyn Chu Caroline Stefani Mridu Acharya Jessica A Hamerman Adam Lacy-Hulbert Source Type: research
Disruption of IFN γ, GZMB, PRF1, or LYST Results in Reduced Suppressive Function in Human CD8+ T Cells
In this study, we further investigated the importance of IFNγ-, GZMB-, PRF1-, and LYST-associated pathways in CD8+ T cell-mediated suppression. Using the CRISPR-Cas9 ribonucleoprotein transfection system, we first optimized efficient gene knockout while maintaining high viability in primary bulk human CD8+ T cells. Knockout was confirmed through quantitative real-time PCR assays in all cases, combined with flow cytometry where appropriate, as well as confirmation of insertions and/or deletions at genomic target sites. We observed that the knockout of IFNγ, GZMB, PRF1, or LYST, but not the knockout of IL4 or IL5, resulted...
Source: Journal of Immunology - April 12, 2024 Category: Allergy & Immunology Authors: Chakrapani Vemulawada Pranav S Renavikar Michael P Crawford Scott Steward-Tharp Nitin J Karandikar Source Type: research
The Transcription Factor Zfp335 Promotes Differentiation and Survival of Effector Th1 Cells by Directly Regulating Lmna Expression
In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter ...
Source: Journal of Immunology - April 10, 2024 Category: Allergy & Immunology Authors: Haiyan Liu Zhao Feng Anjun Jiao Linbo Lan Renyi Ding Wenhua Li Huiqiang Zheng Yanhong Su Xiaoxuan Jia Dan Zhang Xiaofeng Yang Lianjun Zhang Lina Sun Baojun Zhang Source Type: research
The Transcription Factor Zfp335 Promotes Differentiation and Survival of Effector Th1 Cells by Directly Regulating Lmna Expression
In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter ...
Source: Journal of Immunology - April 10, 2024 Category: Allergy & Immunology Authors: Haiyan Liu Zhao Feng Anjun Jiao Linbo Lan Renyi Ding Wenhua Li Huiqiang Zheng Yanhong Su Xiaoxuan Jia Dan Zhang Xiaofeng Yang Lianjun Zhang Lina Sun Baojun Zhang Source Type: research
The Transcription Factor Zfp335 Promotes Differentiation and Survival of Effector Th1 Cells by Directly Regulating Lmna Expression
In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter ...
Source: Journal of Immunology - April 10, 2024 Category: Allergy & Immunology Authors: Haiyan Liu Zhao Feng Anjun Jiao Linbo Lan Renyi Ding Wenhua Li Huiqiang Zheng Yanhong Su Xiaoxuan Jia Dan Zhang Xiaofeng Yang Lianjun Zhang Lina Sun Baojun Zhang Source Type: research
Altering β Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice
In this study, we manipulated β cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the β cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated β cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 ...
Source: Journal of Immunology - April 8, 2024 Category: Allergy & Immunology Authors: David J De George Gaurang Jhala Claudia Selck Prerak Trivedi Thomas C Brodnicki Leanne Mackin Thomas W Kay Helen E Thomas Balasubramanian Krishnamurthy Source Type: research
Altering β Cell Antigen Exposure to Exhausted CD8+ T Cells Prevents Autoimmune Diabetes in Mice
In this study, we manipulated β cell Ag presentation to target exhausted autoreactive T cells by inhibiting IFN-γ-mediated MHC class I upregulation or by ectopically expressing the β cell Ag IGRP under the MHC class II promotor in the NOD8.3 model. Islet PD-1+TIM3+CD8+ (terminally exhausted [TEX]) cells were primary producers of islet granzyme B and CD107a, suggestive of cells that have entered the exhaustion program yet maintained cytotoxic capacity. Loss of IFN-γ-mediated β cell MHC class I upregulation correlated with a significant reduction in islet TEX cells and diabetes protection in NOD8.3 mice. In NOD.TII/8.3 ...
Source: Journal of Immunology - April 8, 2024 Category: Allergy & Immunology Authors: David J De George Gaurang Jhala Claudia Selck Prerak Trivedi Thomas C Brodnicki Leanne Mackin Thomas W Kay Helen E Thomas Balasubramanian Krishnamurthy Source Type: research
Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis
J Immunol. 2024 Apr 5:ji2300751. doi: 10.4049/jimmunol.2300751. Online ahead of print.ABSTRACTLong-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmun...
Source: Journal of Immunology - April 5, 2024 Category: Allergy & Immunology Authors: Connor Frank Hannah E Salapa Kevin J H Allen Michael C Levin Wojciech Dawicki Ekaterina Dadachova Source Type: research
NK Cell-Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19
J Immunol. 2024 Apr 5:ji2300731. doi: 10.4049/jimmunol.2300731. Online ahead of print.ABSTRACTNK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-β, that underlie this dysregulation. However, the role of cell-cell interactions in modulating NK cell function during COVID-19 remains unclear. To address this question, we combined cell-cell communication analysis on existing single-cell RNA sequencing data with in vitro primary cell coculture experiments to dissect the m...
Source: Journal of Immunology - April 5, 2024 Category: Allergy & Immunology Authors: Madeline J Lee Izumi de Los Rios Kobara Trisha R Barnard Xariana Vales Torres Nicole H Tobin Kathie G Ferbas Anne W Rimoin Otto O Yang Grace M Aldrovandi Aaron J Wilk Jennifer A Fulcher Catherine A Blish Source Type: research
Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis
J Immunol. 2024 Apr 5:ji2300751. doi: 10.4049/jimmunol.2300751. Online ahead of print.ABSTRACTLong-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmun...
Source: Journal of Immunology - April 5, 2024 Category: Allergy & Immunology Authors: Connor Frank Hannah E Salapa Kevin J H Allen Michael C Levin Wojciech Dawicki Ekaterina Dadachova Source Type: research
NK Cell-Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19
J Immunol. 2024 Apr 5:ji2300731. doi: 10.4049/jimmunol.2300731. Online ahead of print.ABSTRACTNK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-β, that underlie this dysregulation. However, the role of cell-cell interactions in modulating NK cell function during COVID-19 remains unclear. To address this question, we combined cell-cell communication analysis on existing single-cell RNA sequencing data with in vitro primary cell coculture experiments to dissect the m...
Source: Journal of Immunology - April 5, 2024 Category: Allergy & Immunology Authors: Madeline J Lee Izumi de Los Rios Kobara Trisha R Barnard Xariana Vales Torres Nicole H Tobin Kathie G Ferbas Anne W Rimoin Otto O Yang Grace M Aldrovandi Aaron J Wilk Jennifer A Fulcher Catherine A Blish Source Type: research
