Differences in host immune populations between rhesus macaques and cynomolgus macaque subspecies in relation to susceptibility to Mycobacterium tuberculosis infection

AbstractRhesus (Macaca mulatta) and cynomolgus (Macaca fasicularis) macaques of distinct genetic origin are understood to vary in susceptibility to Mycobacterium tuberculosis, and therefore differences in their immune systems may account for the differences in disease control. Monocyte:lymphocyte (M:L) ratio has been identified as a risk factor for M. tuberculosis infection and is known to vary between macaque species. We aimed to characterise the constituent monocyte and lymphocyte populations between macaque species, and profile other major immune cell subsets including: CD4+ and CD8+ T-cells, NK-cells, B-cells, monocyte subsets and myeloid dendritic cells. We found immune cell subsets to vary significantly between macaque species. Frequencies of CD4+ and CD8+ T-cells and the CD4:CD8 ratio showed significant separation between species, while myeloid dendritic cells best associated macaque populations by M. tuberculosis susceptibility. A more comprehensive understanding of the immune parameters between macaque species may contribute to the identification of new biomarkers and correlates of protection.

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Differences in Host Immune Populations Between Rhesus Macaques and Cynomolgus Macaque Subspecies, in Relation to Susceptibility to Mycobacterium Tuberculosis Infection.

10.21203/rs.3.rs-252046/v1 ◽

2021 ◽

Author(s):

Laura Sibley ◽

Owen Daykin-Pont ◽

Charlotte Sarfas ◽

Jordan Pascoe ◽

Alexandra Morrison ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

Immune Cell ◽

Rhesus Macaques ◽

Cynomolgus Macaque ◽

Myeloid Dendritic Cells ◽

Mycobacterium Tuberculosis Infection ◽

Macaque Species ◽

Immune Cell Subsets

Abstract Rhesus (Macaca mulatta) and cynomolgus (Macaca fasicularis) macaques of distinct genetic origin are understood to vary in susceptibility to Mycobacterium tuberculosis, and therefore differences in their immune systems may account for the differences in disease control. Monocyte:lymphocyte (M:L) ratio has been identified as a risk factor for M. tuberculosis infection and is known to vary between macaque species. We aimed to characterise the constituent monocyte and lymphocyte populations between macaque species, and profile other major immune cell subsets including: CD4+ and CD8+ T-cells, NK-cells, B-cells, monocyte subsets and myeloid dendritic cells. We found immune cell subsets to vary significantly between macaque species. Frequencies of CD4+ and CD8+ T-cells and the CD4:CD8 ratio showed significant separation between species, while myeloid dendritic cells best associated macaque populations by M. tuberculosis susceptibility. A more comprehensive understanding of the immune parameters between macaque species may contribute to the identification of new biomarkers and correlates of protection.

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PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Science Immunology ◽

10.1126/sciimmunol.abf3861 ◽

2021 ◽

Vol 6 (55) ◽

pp. eabf3861

Author(s):

Keith D. Kauffman ◽

Shunsuke Sakai ◽

Nickiana E. Lora ◽

Sivaranjani Namasivayam ◽

Paul J. Baker ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cell Function ◽

Immune Cell ◽

Rhesus Macaques ◽

Imaging Studies ◽

Chronic Infections ◽

Mycobacterium Tuberculosis Infection ◽

Cell Responses

Boosting immune cell function by targeting the coinhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here, we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with anti–PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared with isotype control–treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in anti–PD-1–treated macaques were not increased in number or function in granulomas, expressed increased levels of CTLA-4, and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of anti–PD-1–treated animals, multiple proinflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Last, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota before infection in individual macaques. Therefore, PD-1–mediated coinhibition is required for control of Mtb infection in macaques, perhaps because of its role in dampening detrimental inflammation and allowing for normal CD4 T cell responses.

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PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

10.1101/2020.08.05.237883 ◽

2020 ◽

Author(s):

Keith D Kauffman ◽

Shunsuke Sakai ◽

Nickiana E Lora ◽

Sivaranjani Namasivayam ◽

Paul J Baker ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cell Function ◽

Immune Cell ◽

Rhesus Macaques ◽

Chronic Infections ◽

Mycobacterium Tuberculosis Infection ◽

Cell Responses ◽

Pro Inflammatory Cytokines

ABSTRACTBoosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with αPD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in αPD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of αPD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.

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TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.649135 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenyan Fu ◽

Renfei Cai ◽

Zetong Ma ◽

Tian Li ◽

Changhai Lei ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Cell ◽

Therapeutic Potential ◽

Interleukin 10 ◽

Immunological Tolerance ◽

Tolerogenic Dendritic Cells ◽

Immune Cell Subsets ◽

Pregnant Mice ◽

Antigen Presenting

The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4+ T cells toward a classic TH2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

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Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

10.1101/2020.03.09.981019 ◽

2020 ◽

Cited By ~ 1

Author(s):

Uma Shanmugasundaram ◽

Allison N Bucsan ◽

Shashank R. Ganatra ◽

Chris Ibegbu ◽

Melanie Quezada ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection ◽

Double Positive ◽

Cell Responses ◽

Ifn Γ

AbstractMycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and memory CD4 and CD8 T cells producing IFN-γ in the airways compared to peripheral blood, which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-17/IFN-γ double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb burden. Our findings provide novel insights into antigen-specific T cell responses associated with asymptomatic Mtb infection that are relevant for developing better strategies to control TB.

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Immunological changes following intraperitoneal administration of a formulated IL-12 plasmid in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.156 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 156-156

Author(s):

Khursheed Anwer ◽

Junko Matsuzaki ◽

Wiam Bshara ◽

Amit Lugade ◽

Angela Omilian ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Cell ◽

Cytotoxic T Lymphocyte ◽

Intraperitoneal Administration ◽

Cell Populations ◽

Newly Diagnosed ◽

Myeloid Dendritic Cells ◽

Peritoneal Cancer ◽

Circulating T Cells

156 Background: The translational component of a Phase I study of weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). Our hypothesis is that the GEN-1 plus NAC treatment will reprogram the tumor immune microenvironment towards a potent antitumor immune response. Methods: Patients received GEN-1 at escalating dose levels from 36 mg/m2, 47 mg/m2, 61 mg/m2, to 79 mg/m2weekly for 8 treatments with concurrent T/C. Tumor samples collected at time of diagnostic laparoscopy and interval debulking (IDB). Blood and peritoneal ascites were collected before and after treatment. The immunological analysis included frequency of immune cell populations and cytokine levels in tumor, blood, and peritoneal ascites and cell-specific mRNA expression profile. Results: The preliminary results obtained from first two cohorts show that GEN-1 may be enhancing post-treatment changes in immune cell populations including an increase in cytotoxic CD8+ T-cells and decrease in immunosuppressive FoxP3+ T-reg cells in tumor at IDB. The CD8:Foxp3 ratio appeared to be skewing beneficially towards more cytotoxic T lymphocyte and away from suppressive cells in most patients. The analysis of circulating immune cells 21 days after first GEN-1 treatment showed a decrease in circulating CD123+ plasmacytoid dendritic cells, but no change in CD11c+ myeloid dendritic cells. There were no major changes in the frequency of circulating T-cells. Additional analyses from this study are in progress. Conclusions: Based on preliminary analyses of cohorts 1 & 2 samples analyzed, the treatment of EOC patients with GEN-1 and NAC has resulted in favorable immunological responses. Updated results to be presented at meeting. Clinical trial information: NCT02480374.

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Myeloid dendritic cells isolated from tissues of SIV-infected Rhesus macaques promote the induction of regulatory T cells

AIDS ◽

10.1097/qad.0b013e32834ed8df ◽

2012 ◽

Vol 26 (3) ◽

pp. 263-273 ◽

Cited By ~ 26

Author(s):

Pietro Presicce ◽

Julia M. Shaw ◽

Christopher J. Miller ◽

Barbara L. Shacklett ◽

Claire A. Chougnet

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Rhesus Macaques ◽

Myeloid Dendritic Cells

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Limited Pulmonary Mucosal-Associated Invariant T Cell Accumulation and Activation during Mycobacterium tuberculosis Infection in Rhesus Macaques

Infection and Immunity ◽

10.1128/iai.00431-18 ◽

2018 ◽

Vol 86 (12) ◽

Cited By ~ 16

Author(s):

Keith D. Kauffman ◽

Michelle A. Sallin ◽

Stella G. Hoft ◽

Shunsuke Sakai ◽

Rashida Moore ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

Intracellular Cytokine Staining ◽

Mycobacterium Tuberculosis Infection ◽

Content Type ◽

Mait Cells ◽

Cd69 Expression

ABSTRACT Mucosal-associated invariant T cells (MAITs) are positioned in airways and may be important in the pulmonary cellular immune response against Mycobacterium tuberculosis infection, particularly prior to priming of peptide-specific T cells. Accordingly, there is interest in the possibility that boosting MAITs through tuberculosis (TB) vaccination may enhance protection, but MAIT responses in the lungs during tuberculosis are poorly understood. In this study, we compared pulmonary MAIT and peptide-specific CD4 T cell responses in M. tuberculosis-infected rhesus macaques using 5-OP-RU-loaded MR-1 tetramers and intracellular cytokine staining of CD4 T cells following restimulation with an M. tuberculosis-derived epitope megapool (MTB300), respectively. Two of four animals showed a detectable increase in the number of MAIT cells in airways at later time points following infection, but by ∼3 weeks postexposure, MTB300-specific CD4 T cells arrived in the airways and greatly outnumbered MAITs thereafter. In granulomas, MTB300-specific CD4 T cells were ∼20-fold more abundant than MAITs. CD69 expression on MAITs correlated with tissue residency rather than bacterial loads, and the few MAITs found in granulomas poorly expressed granzyme B and Ki67. Thus, MAIT accumulation in the airways is variable and late, and MAITs display little evidence of activation in granulomas during tuberculosis in rhesus macaques.

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Immune Monitoring during Therapy Reveals Activitory and Regulatory Immune Responses in High-Risk Neuroblastoma

Cancers ◽

10.3390/cancers13092096 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2096

Author(s):

Celina L. Szanto ◽

Annelisa M. Cornel ◽

Sara M. Tamminga ◽

Eveline M. Delemarre ◽

Coco C. H. de Koning ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Nk Cells ◽

Immune Cell ◽

High Dose Chemotherapy ◽

Immune Monitoring ◽

High Dose ◽

Effector Cells ◽

Gm Csf ◽

Immune Cell Subsets

Despite intensive treatment, including consolidation immunotherapy (IT), prognosis of high-risk neuroblastoma (HR-NBL) is poor. Immune status of patients over the course of treatment, and thus immunological features potentially explaining therapy efficacy, are largely unknown. In this study, the dynamics of immune cell subsets and their function were explored in 25 HR-NBL patients at diagnosis, during induction chemotherapy, before high-dose chemotherapy, and during IT. The dynamics of immune cells varied largely between patients. IL-2- and GM-CSF-containing IT cycles resulted in significant expansion of effector cells (NK-cells in IL-2 cycles, neutrophils and monocytes in GM-CSF cycles). Nonetheless, the cytotoxic phenotype of NK-cells was majorly disturbed at the start of IT, and both IL-2 and GM-CSF IT cycles induced preferential expansion of suppressive regulatory T-cells. Interestingly, proliferative capacity of purified patient T-cells was impaired at diagnosis as well as during therapy. This study indicates the presence of both immune-enhancing as well as regulatory responses in HR-NBL patients during (immuno)therapy. Especially the double-edged effects observed in IL-2-containing IT cycles are interesting, as this potentially explains the absence of clinical benefit of IL-2 addition to IT cycles. This suggests that there is a need to combine anti-GD2 with more specific immune-enhancing strategies to improve IT outcome in HR-NBL.

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