Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.75.44
Theresa L. Chang, Annie Wang, Alisa C Herbst, Cyril Hernandez, Jeet Vaishnav, A. Lemenze, S. Swaminathan, Michelle Dalla Piazza, D. Finkel, S. Bentsianov, N. Roche
Transgender people are at greater risk than cisgender people of acquiring HIV and other sexually transmitted infections. Globally, the risk of acquiring HIV infection is nearly 49 times higher in transgender women than in other populations. Although behavioral and psychosocial factors contribute to the higher HIV risk in transgender people, gender-affirming hormone (GAH) (i.e., testosterone for transgender individuals assigned female at birth or estrogen/antiandrogen for transgender individuals assigned male at birth) may alter immune cell functions, resulting in increased HIV transmission. We have profiled gene expression of PBMCs from transgender females and males and have identified four specific genes (MTND1P23, IGSF10, MSR1, and DUXAP9) that were differentially expressed in transgender females. Among these genes, macrophage scavenger receptor 1 was down-regulated 0.5- or 0.4-fold compared to cis females and cis males, respectively. Transient expression of MSR1 suppressed in vitro HIV infection, suggesting that MSR1 protects cells against HIV. The data indicate that down-regulation of MSR1 in transgender women may play a role in their increased HIV risk. Future studies on the mechanisms by which MRS1 inhibits HIV infection may offer new strategies for HIV prevention in transgender women. NIH R21AI55322
{"title":"Macrophage scavenger receptor 1, a suppressor of HIV infection, is down-regulated in transgender females","authors":"Theresa L. Chang, Annie Wang, Alisa C Herbst, Cyril Hernandez, Jeet Vaishnav, A. Lemenze, S. Swaminathan, Michelle Dalla Piazza, D. Finkel, S. Bentsianov, N. Roche","doi":"10.4049/jimmunol.210.supp.75.44","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.75.44","url":null,"abstract":"\u0000 Transgender people are at greater risk than cisgender people of acquiring HIV and other sexually transmitted infections. Globally, the risk of acquiring HIV infection is nearly 49 times higher in transgender women than in other populations. Although behavioral and psychosocial factors contribute to the higher HIV risk in transgender people, gender-affirming hormone (GAH) (i.e., testosterone for transgender individuals assigned female at birth or estrogen/antiandrogen for transgender individuals assigned male at birth) may alter immune cell functions, resulting in increased HIV transmission. We have profiled gene expression of PBMCs from transgender females and males and have identified four specific genes (MTND1P23, IGSF10, MSR1, and DUXAP9) that were differentially expressed in transgender females. Among these genes, macrophage scavenger receptor 1 was down-regulated 0.5- or 0.4-fold compared to cis females and cis males, respectively. Transient expression of MSR1 suppressed in vitro HIV infection, suggesting that MSR1 protects cells against HIV. The data indicate that down-regulation of MSR1 in transgender women may play a role in their increased HIV risk. Future studies on the mechanisms by which MRS1 inhibits HIV infection may offer new strategies for HIV prevention in transgender women.\u0000 NIH R21AI55322","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75646428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.221.30
Viva J Rasé, E. Kolawole, Baoyu Liu, Cory M. Ayres, Jhordan Rogers, K. Salaita, B. Baker, B. Evavold
There are three isoforms of Beta2 microglobulin (B2m) identified in mice and they differ by a single amino acid residue. To study how B2m can modify the peptide binding pocket of MHCI we turned to the comparison of mouse (mB2m) and human (hB2m). It is known that hB2m forms more stable with mouse MHCI heavy chain as compared to mb2m and hB2m is often the choice for most pMHCI tetramer production. Analysis of mB2m and hB2m tetramer (GP33 41M) following LCMV infection revealed no difference in percentage of tetramer positive cells but an increase was observed in staining intensity (MFI) of hB2m. Using steered molecular dynamics we found that there were allosteric effects with mB2m displaying more movement within the binding pocket than hB2m. Consistent with this we saw increased 2D affinity for antigen MHC D band K bhB2m complexes for OT1 and P14 TCRs, respectively. We also measured the force effects on bond lifetime between TCR and pMHC using biomembrane force probe (BFP) and DNA tension sensor. For OTI, we found that mB2m complexes had a longer bond lifetime measured by both methods. We observed signaling and functional effects consistent with the 2D affinity and bond lifetime measurements in mouse verses human B2m. For example, mB2m leads to increased levels of activated LCK (pY394/505) in OT1 T cells. Therefore, alterations in B2m effect the distal peptide binding domain of MHCI and suggests dynamic allostery may influence antigen recognition by TCR. 5T32NS115664-03 5R01AI147641-03
{"title":"Human versus mouse Beta 2 microglobulin alters TCR antigen recognition kinetics with mouse MHCI","authors":"Viva J Rasé, E. Kolawole, Baoyu Liu, Cory M. Ayres, Jhordan Rogers, K. Salaita, B. Baker, B. Evavold","doi":"10.4049/jimmunol.210.supp.221.30","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.221.30","url":null,"abstract":"\u0000 There are three isoforms of Beta2 microglobulin (B2m) identified in mice and they differ by a single amino acid residue. To study how B2m can modify the peptide binding pocket of MHCI we turned to the comparison of mouse (mB2m) and human (hB2m). It is known that hB2m forms more stable with mouse MHCI heavy chain as compared to mb2m and hB2m is often the choice for most pMHCI tetramer production. Analysis of mB2m and hB2m tetramer (GP33 41M) following LCMV infection revealed no difference in percentage of tetramer positive cells but an increase was observed in staining intensity (MFI) of hB2m. Using steered molecular dynamics we found that there were allosteric effects with mB2m displaying more movement within the binding pocket than hB2m. Consistent with this we saw increased 2D affinity for antigen MHC D band K bhB2m complexes for OT1 and P14 TCRs, respectively. We also measured the force effects on bond lifetime between TCR and pMHC using biomembrane force probe (BFP) and DNA tension sensor. For OTI, we found that mB2m complexes had a longer bond lifetime measured by both methods. We observed signaling and functional effects consistent with the 2D affinity and bond lifetime measurements in mouse verses human B2m. For example, mB2m leads to increased levels of activated LCK (pY394/505) in OT1 T cells. Therefore, alterations in B2m effect the distal peptide binding domain of MHCI and suggests dynamic allostery may influence antigen recognition by TCR.\u0000 5T32NS115664-03 5R01AI147641-03","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"201 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75662563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.223.07
Kenna Nagy, Lisa Kain, R. Stanfield, C. Grimes, I. Wilson, P. Savage, MG Finn, L. Teyton
Antibiotic resistance threatens clinical control of bacterial infections while the genetic adaptability of microbes continues to outpace small-molecule development. The combinatorial diversity of antibodies offers a solution to this problem. However, under normal circumstances the polymeric glycans of bacterial surfaces avoid adaptive recognition by not binding to MHC molecules. Thus, they are T cell independent antigens and targeted only by low affinity IgM responses. Glycoconjugate vaccines have been developed to provide bystander T cell help to overcome this limitation but have failed to elicit protective responses against antibiotic resistant Staphylococcus aureus in clinical trials. To address limitations in current conjugate vaccine approaches, we optimized anti-glycan B cell help through three convergent prongs: exploiting cognate T cell help, using a B cell-centric adjuvant, and using synthetic minimal glycans. This prototype next generation conjugate vaccine was used to produce nanomolar affinity anti-glycan responses in proof-of-concept studies. Focusing on antibiotic resistant Staphylococcus aureus three glycan targets of the cell wall and bacterial capsule have been selected and used to produce monoclonal antibodies. These antibodies were characterized structurally, biophysically, and by B cell sequencing to confirm high affinity, maturation, and specificity towards the intended targets. The potential therapeutic benefits are currently being tested in three preclinical mouse models: skin, lung, and systemic infection, using passive and active immunization. Preliminary studies have shown therapeutic efficacy in both a preventative and interventional model for some of these antibodies. Kenna Nagy supported by: NIH TL1TR002551 For this project P.I. Luc Teyton supported by: NIH U01 AI160338, NIH R01 AI139748
{"title":"Therapeutic anti-glycan antibodies against antibiotic resistant Staphylococcus aureus","authors":"Kenna Nagy, Lisa Kain, R. Stanfield, C. Grimes, I. Wilson, P. Savage, MG Finn, L. Teyton","doi":"10.4049/jimmunol.210.supp.223.07","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.223.07","url":null,"abstract":"\u0000 Antibiotic resistance threatens clinical control of bacterial infections while the genetic adaptability of microbes continues to outpace small-molecule development. The combinatorial diversity of antibodies offers a solution to this problem. However, under normal circumstances the polymeric glycans of bacterial surfaces avoid adaptive recognition by not binding to MHC molecules. Thus, they are T cell independent antigens and targeted only by low affinity IgM responses. Glycoconjugate vaccines have been developed to provide bystander T cell help to overcome this limitation but have failed to elicit protective responses against antibiotic resistant Staphylococcus aureus in clinical trials. To address limitations in current conjugate vaccine approaches, we optimized anti-glycan B cell help through three convergent prongs: exploiting cognate T cell help, using a B cell-centric adjuvant, and using synthetic minimal glycans. This prototype next generation conjugate vaccine was used to produce nanomolar affinity anti-glycan responses in proof-of-concept studies. Focusing on antibiotic resistant Staphylococcus aureus three glycan targets of the cell wall and bacterial capsule have been selected and used to produce monoclonal antibodies. These antibodies were characterized structurally, biophysically, and by B cell sequencing to confirm high affinity, maturation, and specificity towards the intended targets. The potential therapeutic benefits are currently being tested in three preclinical mouse models: skin, lung, and systemic infection, using passive and active immunization. Preliminary studies have shown therapeutic efficacy in both a preventative and interventional model for some of these antibodies.\u0000 Kenna Nagy supported by: NIH TL1TR002551 For this project P.I. Luc Teyton supported by: NIH U01 AI160338, NIH R01 AI139748","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74499262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.243.10
H. Nagashima, Justin Shayne, Y. Kanno, J. O’Shea
The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a tandem multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites, promoting tissue repair as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. However, how those two related but distinct type 2 lymphocytes configure the extended type 2 cytokine loci and elicit selective output of this cassette genes is not well understood. Here, we took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13and Il5loci were aligned in proximity whereas Il4locus was insulated. In Th2 cells, Il4and Il13positioned in proximity while the Il5locus remained distal. Select REs were separately deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.
{"title":"Distinct 3D remodeling of Il4-Il13-Il5loci mediates differential type 2 responses in innate versus adaptive lymphocytes","authors":"H. Nagashima, Justin Shayne, Y. Kanno, J. O’Shea","doi":"10.4049/jimmunol.210.supp.243.10","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.243.10","url":null,"abstract":"\u0000 The type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13 reside within a tandem multi-gene cluster in mammals. These cytokines represent the hallmark of type 2 immune responses controlling parasites, promoting tissue repair as well as causing allergic diseases. Both innate and adaptive lymphocytes secrete type 2 cytokines with discordant production spectra. However, how those two related but distinct type 2 lymphocytes configure the extended type 2 cytokine loci and elicit selective output of this cassette genes is not well understood. Here, we took a holistic structural and functional view of the type 2 cytokine locus before and after activation, comparing innate (ILC2) and adaptive (Th2) lymphocytes to understand mechanisms underlying their distinctive programs. Rapid induction of IL-5 dominates in ILC2, whereas IL-4 does so in Th2 cells. Using high-resolution chromatin conformation capture we found that global cellular chromatin architecture remained constant, whereas the type 2 cytokine locus rapidly remodeled. In ILC2, Il13and Il5loci were aligned in proximity whereas Il4locus was insulated. In Th2 cells, Il4and Il13positioned in proximity while the Il5locus remained distal. Select REs were separately deleted in mice to confirm cell-type specific and activation-dependent roles in type 2 responses in vivo. Thus, contrary to the premise that chromatin architecture plays a minimal role in steady-state gene induction, signal-dependent remodeling of 3D configuration underlies the discordant cytokine outputs in ILC2s versus Th2 cells.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74655947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.234.08
C. Barnes, M. Abernathy
Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, the emergence of SARS-CoV-2 variants have diminished the efficacy of almost all antiviral monoclonal antibodies. Moreover, most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses and the larger Orthocoronavirinae subfamily. Thus, continued development of immunotherapies resilient to SARS-CoV-2 viral evolution, and capable of recognizing zoonotic coronaviruses with spillover potential is necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. We identified and structurally-characterized neutralizing antibodies to the fusion peptide, to the stem helix near the heptad repeat 2 region and to subdomain 1 of the spike glycoprotein, that are broadly cross-reactive and protective in vivo. Collectively, our data adds to the growing body of evidence suggesting the potential use of broadly neutralizing antibodies for prophylaxis or therapy against emerging SARS-CoV-2 VOC and future zoonotic spillover events. C.O.B. is supported by the Howard Hughes Medical Institute Hanna Gray Fellowship and is a Chan Zuckerberg Biohub investigator.
{"title":"Structural insights into human monoclonal antibodies with pan-coronavirus reactivity","authors":"C. Barnes, M. Abernathy","doi":"10.4049/jimmunol.210.supp.234.08","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.234.08","url":null,"abstract":"\u0000 Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, the emergence of SARS-CoV-2 variants have diminished the efficacy of almost all antiviral monoclonal antibodies. Moreover, most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses and the larger Orthocoronavirinae subfamily. Thus, continued development of immunotherapies resilient to SARS-CoV-2 viral evolution, and capable of recognizing zoonotic coronaviruses with spillover potential is necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. We identified and structurally-characterized neutralizing antibodies to the fusion peptide, to the stem helix near the heptad repeat 2 region and to subdomain 1 of the spike glycoprotein, that are broadly cross-reactive and protective in vivo. Collectively, our data adds to the growing body of evidence suggesting the potential use of broadly neutralizing antibodies for prophylaxis or therapy against emerging SARS-CoV-2 VOC and future zoonotic spillover events.\u0000 C.O.B. is supported by the Howard Hughes Medical Institute Hanna Gray Fellowship and is a Chan Zuckerberg Biohub investigator.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74691601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.89.14
C. A. Herne, Jennifer E. Bruno, A. Baran, Derick R. Peterson, T. Mosmann, S. Quataert, A. Evans, C. Zent, Charles C Chu
T cell dysregulation has been observed in many tumors, but has not been well-characterized in rare B-cell splenic lymphomas. We began defining the T cell populations in the tumor microenvironments of four human indolent B cell splenic lymphomas: splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), hairy cell leukemia variant (HCLv), and splenic diffuse red pulp small B-cell lymphoma (SDRPL). After Institutional Research Subjects Review Board approval, we studied de-identified cryopreserved bulk splenic tumor suspension cell isolates from fresh (less than 4 h) splenectomy tissue and matched intact formalin-fixed paraffin embedded (FFPE) tissue sections from 17 splenic lymphoma patients and 4 trauma patients (controls). Initial immunohistochemical staining analysis of FFPE tissue sections suggests that the distribution of intratumoral T cells is markedly different among B cell splenic lymphomas. In HCL, residual T cell zones appear retained, albeit diminished, while HCLv and SDRPL have markedly reduced T cells throughout with non-distinct zonation, and SMZL has prominent peritumoral collections of T cells at the interface of the neoplastic white pulp. High-parameter (32-color) fluorescence spectral flow cytometry (Cytek Aurora) analysis suggests that splenic lymphomas exhibit CD4+ and CD8+ T cells with higher proportions of transitional memory, regulatory, and exhausted phenotypes than controls. T cell activation may be enhanced in HCLv. HCLv and SMZL may have decreased naïve T cells. Finally, splenic lymphomas had higher proportions of T cells with an exhausted phenotype compared to trauma samples. In summary, our data suggests T cells are dysregulated in B-cell splenic lymphomas. American Association of Immunologists, Hairy Cell Leukemia Foundation / Sass Foundation for Medical Research, and generous donations by Elizabeth Aaron.
{"title":"Indolent B-cell splenic lymphomas have T cells with an exhausted phenotype","authors":"C. A. Herne, Jennifer E. Bruno, A. Baran, Derick R. Peterson, T. Mosmann, S. Quataert, A. Evans, C. Zent, Charles C Chu","doi":"10.4049/jimmunol.210.supp.89.14","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.89.14","url":null,"abstract":"\u0000 T cell dysregulation has been observed in many tumors, but has not been well-characterized in rare B-cell splenic lymphomas. We began defining the T cell populations in the tumor microenvironments of four human indolent B cell splenic lymphomas: splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), hairy cell leukemia variant (HCLv), and splenic diffuse red pulp small B-cell lymphoma (SDRPL). After Institutional Research Subjects Review Board approval, we studied de-identified cryopreserved bulk splenic tumor suspension cell isolates from fresh (less than 4 h) splenectomy tissue and matched intact formalin-fixed paraffin embedded (FFPE) tissue sections from 17 splenic lymphoma patients and 4 trauma patients (controls). Initial immunohistochemical staining analysis of FFPE tissue sections suggests that the distribution of intratumoral T cells is markedly different among B cell splenic lymphomas. In HCL, residual T cell zones appear retained, albeit diminished, while HCLv and SDRPL have markedly reduced T cells throughout with non-distinct zonation, and SMZL has prominent peritumoral collections of T cells at the interface of the neoplastic white pulp. High-parameter (32-color) fluorescence spectral flow cytometry (Cytek Aurora) analysis suggests that splenic lymphomas exhibit CD4+ and CD8+ T cells with higher proportions of transitional memory, regulatory, and exhausted phenotypes than controls. T cell activation may be enhanced in HCLv. HCLv and SMZL may have decreased naïve T cells. Finally, splenic lymphomas had higher proportions of T cells with an exhausted phenotype compared to trauma samples. In summary, our data suggests T cells are dysregulated in B-cell splenic lymphomas.\u0000 American Association of Immunologists, Hairy Cell Leukemia Foundation / Sass Foundation for Medical Research, and generous donations by Elizabeth Aaron.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74887900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.221.11
Luciano Mazzoccoli, Stephen Iwanowycz, S. Ngoi, Megan Hill, Bei Liu
Dendritic cells (DCs) are central regulators of the adaptive immune response, thereupon necessary for T cell-mediated cancer immunity. To improve anti-tumor response, strategies to stimulate T cell response create new opportunities in DC cell biology, where DC maturation and antigen presentation are paramount. DC1 subtype is known for antigen-cross presentation to CD8 +T cells and the DC2 subtype to CD4 +T-cells. Previous studies showed that the immune chaperone GP96 plays a pivotal role in the processes of innate receptors. As a subject of interest from our lab, the GP96 client network offers potential targets to be explored for improving DC functions. We reported an increase in DC2 infiltration on the tumor side and a reduction of tumor growth in DC-specific GP96 deficient mice. Notwithstanding, the mechanism of GP96 in regulating DC functions is the subject of our study. By using in vitro approach, our study shows improvement in DC differentiation through gene expression assay, where DC subtypes display differential dependence on ER chaperone proteins. Also, the deletion of GP96 in DCs improves immunostimulatory activation and inhibits regulatory functions. Lastly, GP96 deficient DCs increased OVA antigen uptake and showed less T-cell exhaustion profile from in vivo tumor model. Directly DC activation or bypassing regulatory pathways can unleash T-cell response. Our study provides new insights into the role of GP96 in DCs in directing adaptive immune responses in the tumor microenvironment. This work was supported by the Pelotonia Institute of Immuno-Oncology (PIIO). The work was also supported in part by NIH/NCI (CA193939) and NIH/NIAID (AI125859) and supported by the Flow Cytometry Shared Resource at The Ohio State University Comprehensive Cancer Center and NIH/NCI P30 (CA138313).
{"title":"Immune chaperone modulates dendritic cell functions in the tumor microenvironment","authors":"Luciano Mazzoccoli, Stephen Iwanowycz, S. Ngoi, Megan Hill, Bei Liu","doi":"10.4049/jimmunol.210.supp.221.11","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.221.11","url":null,"abstract":"\u0000 Dendritic cells (DCs) are central regulators of the adaptive immune response, thereupon necessary for T cell-mediated cancer immunity. To improve anti-tumor response, strategies to stimulate T cell response create new opportunities in DC cell biology, where DC maturation and antigen presentation are paramount. DC1 subtype is known for antigen-cross presentation to CD8 +T cells and the DC2 subtype to CD4 +T-cells. Previous studies showed that the immune chaperone GP96 plays a pivotal role in the processes of innate receptors. As a subject of interest from our lab, the GP96 client network offers potential targets to be explored for improving DC functions. We reported an increase in DC2 infiltration on the tumor side and a reduction of tumor growth in DC-specific GP96 deficient mice. Notwithstanding, the mechanism of GP96 in regulating DC functions is the subject of our study. By using in vitro approach, our study shows improvement in DC differentiation through gene expression assay, where DC subtypes display differential dependence on ER chaperone proteins. Also, the deletion of GP96 in DCs improves immunostimulatory activation and inhibits regulatory functions. Lastly, GP96 deficient DCs increased OVA antigen uptake and showed less T-cell exhaustion profile from in vivo tumor model. Directly DC activation or bypassing regulatory pathways can unleash T-cell response. Our study provides new insights into the role of GP96 in DCs in directing adaptive immune responses in the tumor microenvironment.\u0000 This work was supported by the Pelotonia Institute of Immuno-Oncology (PIIO). The work was also supported in part by NIH/NCI (CA193939) and NIH/NIAID (AI125859) and supported by the Flow Cytometry Shared Resource at The Ohio State University Comprehensive Cancer Center and NIH/NCI P30 (CA138313).","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72948313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.245.15
M. Manjili, Madison Isbell, Nicholas Koelsch, F. Mirshahi, Chubquing Guo, M. Idowu, Dana Austin, C. Gelber, Xiang-Yang Wang, A. Sanyal
Recent studies suggest that progression of nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) is associated with a decreased frequency of the hepatic CD4 +T cells, as well as a predominance of the inflammatory immunological pattern. To determine whether the inhibition of chronic inflammation could prevent the progression of NAFLD to HCC, we used a novel LRP-1 agonistic peptide, SP16, during a progressive NAFLD in an animal model of NAFLD, i.e., DIAMOND mice. Tumor progression, circulating inflammatory cytokines as well as the hepatic immune cells were analyzed using 44-plex cytokine array and multi-color flow cytometry. Although SP16 restored the hepatic CD4 +T cells and slightly increased Th2 subset, it failed to modulate the CD4 +Th1 dominant pattern in the liver or prevent HCC. These data suggest that the hepatic immune pattern, which could produce a collective function independent from its cellular components, is more important than CD4 +T cell recovery during disease progression. Our data also suggest that administration of SP16 very early during NAFLD could shift a predominant Th1 pattern towards an equilibrium Th1=Th2=Th17 pattern which has been found to protect DIAMOND mice from from the progression of NAFLD to HCC. Future studies will determine if modulation of the inflammatory immune response by SP16 when administered early during NAFLD progression will prevent HCC. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793, Massey Cancer Center Multi-Investigator Award, grant number 2017-MIP-02, NIH R01DK105961, and VA Merit Award 1I01BX003275. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. Services and products in support of the research project were generated by the Virginia Commonwealth University Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.
{"title":"Restoration of CD4 +T helper cells without modulating the hepatic inflammatory pattern is not sufficient to prevent HCC","authors":"M. Manjili, Madison Isbell, Nicholas Koelsch, F. Mirshahi, Chubquing Guo, M. Idowu, Dana Austin, C. Gelber, Xiang-Yang Wang, A. Sanyal","doi":"10.4049/jimmunol.210.supp.245.15","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.245.15","url":null,"abstract":"\u0000 Recent studies suggest that progression of nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) is associated with a decreased frequency of the hepatic CD4 +T cells, as well as a predominance of the inflammatory immunological pattern. To determine whether the inhibition of chronic inflammation could prevent the progression of NAFLD to HCC, we used a novel LRP-1 agonistic peptide, SP16, during a progressive NAFLD in an animal model of NAFLD, i.e., DIAMOND mice. Tumor progression, circulating inflammatory cytokines as well as the hepatic immune cells were analyzed using 44-plex cytokine array and multi-color flow cytometry. Although SP16 restored the hepatic CD4 +T cells and slightly increased Th2 subset, it failed to modulate the CD4 +Th1 dominant pattern in the liver or prevent HCC. These data suggest that the hepatic immune pattern, which could produce a collective function independent from its cellular components, is more important than CD4 +T cell recovery during disease progression. Our data also suggest that administration of SP16 very early during NAFLD could shift a predominant Th1 pattern towards an equilibrium Th1=Th2=Th17 pattern which has been found to protect DIAMOND mice from from the progression of NAFLD to HCC. Future studies will determine if modulation of the inflammatory immune response by SP16 when administered early during NAFLD progression will prevent HCC.\u0000 This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793, Massey Cancer Center Multi-Investigator Award, grant number 2017-MIP-02, NIH R01DK105961, and VA Merit Award 1I01BX003275. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. Services and products in support of the research project were generated by the Virginia Commonwealth University Flow Cytometry Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73072510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.233.05
J. Moore-Stanley, S. Knight, N. Bakerly, S. Kirkham, Thomas Williams, T. Hussell
Dysregulated inflammation is central to the morbidity and mortality associated with COVID-19. Treatment with dexamethasone and IL-6 blockade can be life-saving in patients stratified for moderate - severe disease. Patients with suppressed immunity are often excluded from immune blockade therapy due to the assumption that additional suppression of an impaired immune system will be detrimental to viral clearance. We hypothesised that patients with suppressed immune systems would be slower to clear viral infection, leading to increased damage and therefore, paradoxically, a more intense acute phase response to SARS-CoV-2 infection. This was tested by a sub-group analysis of the Coronavirus Immune Response and Clinical Outcomes (CIRCO) cohort, an observational study of acute COVID-19 in Greater Manchester, UK. Patients were included if they were treated with dexamethasone and had a research blood sample retrieved within 48 hours of admission, and excluded if they were treated with IL-6 blockade or antiviral therapy prior to research sampling. Acute phase serum cytokine levels were compared between eight immunosuppressed and 12 immunocompetent patients positive for SARS-CoV-2. In support of our hypothesis, we found that immunosuppressed individuals had higher levels of the inflammatory cytokines IP-10 (p=0.03) and MCP-1 (p=0.01) compared to immunocompetent patients matched for COVID-19 severity. This suggests that immunosuppressed patients may benefit as much as immunocompetent individuals from systemic treatments to dampen inflammation in COVID-19, and current recommendations of excluding these patients from treatment solely on the basis of immune competence may need to be re-evaluated.
{"title":"Paradoxically Increased Inflammation in Immunosuppressed Individuals with COVID-19","authors":"J. Moore-Stanley, S. Knight, N. Bakerly, S. Kirkham, Thomas Williams, T. Hussell","doi":"10.4049/jimmunol.210.supp.233.05","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.233.05","url":null,"abstract":"\u0000 Dysregulated inflammation is central to the morbidity and mortality associated with COVID-19. Treatment with dexamethasone and IL-6 blockade can be life-saving in patients stratified for moderate - severe disease. Patients with suppressed immunity are often excluded from immune blockade therapy due to the assumption that additional suppression of an impaired immune system will be detrimental to viral clearance. We hypothesised that patients with suppressed immune systems would be slower to clear viral infection, leading to increased damage and therefore, paradoxically, a more intense acute phase response to SARS-CoV-2 infection. This was tested by a sub-group analysis of the Coronavirus Immune Response and Clinical Outcomes (CIRCO) cohort, an observational study of acute COVID-19 in Greater Manchester, UK. Patients were included if they were treated with dexamethasone and had a research blood sample retrieved within 48 hours of admission, and excluded if they were treated with IL-6 blockade or antiviral therapy prior to research sampling. Acute phase serum cytokine levels were compared between eight immunosuppressed and 12 immunocompetent patients positive for SARS-CoV-2. In support of our hypothesis, we found that immunosuppressed individuals had higher levels of the inflammatory cytokines IP-10 (p=0.03) and MCP-1 (p=0.01) compared to immunocompetent patients matched for COVID-19 severity. This suggests that immunosuppressed patients may benefit as much as immunocompetent individuals from systemic treatments to dampen inflammation in COVID-19, and current recommendations of excluding these patients from treatment solely on the basis of immune competence may need to be re-evaluated.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73087289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-01DOI: 10.4049/jimmunol.210.supp.233.13
Christine M Dang, Akshay Iyer, C. Nelson, Daniel Feaster, David Forrest, Priyanka Ghanta, R. Pahwa, D. Jayaweera, Allan E. Rodriguez, H. Tookes, S. Pallikkuth, S. Pahwa
Opioid dependence is frequent in people with HIV (PWH), but impact of opioids on immune system of PWH is unknown. This study tested the hypothesis that chronic opioid use exacerbates known impairment of flu vaccine responses in PWH. Chronic opioid users were compared to non-opioid users in HIV+ and HIV− groups termed HIV+OP+ (n=28), HIV-OP+ (n=55), HIV+OP− (n=53), HIV-OP− (controls, n=58). HIV+ individuals were on ART with plasma virus load <200 copies/mL. Flu antibody titers were determined at pre- (T0) and 4 weeks post (T2) seasonal quadrivalent influenza vaccinations (2020–2022) by hemagglutination inhibition (HAI) along with a plasma cytokine score at T0. Vaccine response (VR) was defined as a 4-fold change (FC) in titer from T0 to T2. In Kruskal Wallis analysis, all 4 groups had increases in HAI titer from T0 to T2 (p<0.01 to p<0.0001) for antigens (H1N1, H3N2, B Victoria) and whole vaccine. HIV+ status was associated with decreased responses to all antigens but OP+ status in HIV+ and HIV− had higher response than HIV+OP−, both in T2/T0 FC and T2 titer for one or more vaccine antigens (p<0.05 to p<0.001). In regression analysis controlling for demographics, opioid use was associated with increased response to H1N1 and B Yamagata antigens. In a random forest model, predicted probability of VR was lower for HIV+ status and higher for OP+ status. Cytokine score was highest in HIV+OP+. Results of quantitative Ab response to flu vaccine refute our hypothesis that flu vaccine response would be impaired in PWH who chronically use opioids. Qualitative assessments of Ab and mechanism of opioid intersection with B cell function are ongoing to understand if opioid use overcomes humoral immune deficits in PWH.
{"title":"Chronic opioid use is associated with higher flu vaccine induced Ab response in HIV+ and HIV− individuals.","authors":"Christine M Dang, Akshay Iyer, C. Nelson, Daniel Feaster, David Forrest, Priyanka Ghanta, R. Pahwa, D. Jayaweera, Allan E. Rodriguez, H. Tookes, S. Pallikkuth, S. Pahwa","doi":"10.4049/jimmunol.210.supp.233.13","DOIUrl":"https://doi.org/10.4049/jimmunol.210.supp.233.13","url":null,"abstract":"\u0000 Opioid dependence is frequent in people with HIV (PWH), but impact of opioids on immune system of PWH is unknown. This study tested the hypothesis that chronic opioid use exacerbates known impairment of flu vaccine responses in PWH. Chronic opioid users were compared to non-opioid users in HIV+ and HIV− groups termed HIV+OP+ (n=28), HIV-OP+ (n=55), HIV+OP− (n=53), HIV-OP− (controls, n=58). HIV+ individuals were on ART with plasma virus load <200 copies/mL. Flu antibody titers were determined at pre- (T0) and 4 weeks post (T2) seasonal quadrivalent influenza vaccinations (2020–2022) by hemagglutination inhibition (HAI) along with a plasma cytokine score at T0. Vaccine response (VR) was defined as a 4-fold change (FC) in titer from T0 to T2. In Kruskal Wallis analysis, all 4 groups had increases in HAI titer from T0 to T2 (p<0.01 to p<0.0001) for antigens (H1N1, H3N2, B Victoria) and whole vaccine. HIV+ status was associated with decreased responses to all antigens but OP+ status in HIV+ and HIV− had higher response than HIV+OP−, both in T2/T0 FC and T2 titer for one or more vaccine antigens (p<0.05 to p<0.001). In regression analysis controlling for demographics, opioid use was associated with increased response to H1N1 and B Yamagata antigens. In a random forest model, predicted probability of VR was lower for HIV+ status and higher for OP+ status. Cytokine score was highest in HIV+OP+. Results of quantitative Ab response to flu vaccine refute our hypothesis that flu vaccine response would be impaired in PWH who chronically use opioids. Qualitative assessments of Ab and mechanism of opioid intersection with B cell function are ongoing to understand if opioid use overcomes humoral immune deficits in PWH.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73217626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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