scholarly journals Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity

2021 ◽  
Author(s):  
Ying Du ◽  
Nina Hertoghs ◽  
Jason Carnes ◽  
Suzanne M. McDermott ◽  
Maxwell L. Neal ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Malaria Infection ◽  
Vaccine Development ◽  
Inflammatory Responses ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Controlled Human Malaria Infection ◽  
Interferon Responses

Immunization with radiation-attenuated sporozoites (RAS) can confer sterilizing protection against malaria, although the mechanisms behind this protection are incompletely understood. We performed a systems biology analysis of samples from the Immunization by Mosquito with Radiation Attenuated Sporozoites IMRAS) trial, which comprised P. falciparum RAS-immunized (PfRAS), malaria-naive participants whose protection from malaria infection was subsequently assessed by controlled human malaria infection (CHMI). Blood samples collected after initial PfRAS immunization were analyzed to compare immune responses between protected and non-protected volunteers leveraging integrative analysis of whole blood RNA-seq, high parameter flow cytometry, and single cell CITEseq of PBMCs. This analysis revealed differences in early innate immune responses indicating divergent paths associated with protection. In particular, elevated levels of inflammatory responses early after the initial immunization were detrimental for the development of protective adaptive immunity. Specifically, non-classical monocytes and early type I interferon responses induced within 1 day of PfRAS vaccination correlated with impaired immunity. Non-protected individuals also showed an increase in Th2 polarized T cell responses whereas we observed a trend towards increased Th1 and T-bet+ CD8 T cell responses in protected individuals. Temporal differences in genes associated with natural killer cells suggest an important role in immune regulation by these cells. These findings give insight into the immune responses that confer protection against malaria and may guide further malaria vaccine development.

scholarly journals Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

2021 ◽  
Vol 6 (56) ◽  
pp. eabb9435
Author(s):  
Joseph M. Leal ◽  
Jessica Y. Huang ◽  
Karan Kohli ◽  
Caleb Stoltzfus ◽  
Miranda R. Lyons-Cohen ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Critical Role ◽  
Myeloid Cell ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

scholarly journals Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Bobby Brooke Herrera ◽  
Wen-Yang Tsai ◽  
Charlotte A. Chang ◽  
Donald J. Hamel ◽  
Wei-Kung Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dengue Virus ◽  
Zika Virus ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Responses ◽  
T Cell Response ◽  
Zikv Infection ◽  
Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

scholarly journals Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Vasso Apostolopoulos ◽  
Theresia Thalhammer ◽  
Andreas G. Tzakos ◽  
Lily Stojanovska
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Immune Responses ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Dual Function ◽  
Antigen Delivery ◽  
Surface Receptors ◽  
Mhc Molecules ◽  
Cell Responses

Dendritic cells (DCs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. Depending on the method of antigen delivery, DCs stimulate immune responses or induce tolerance. As a consequence of the dual function of DCs, DCs are studied in the context of immunotherapy for both cancer and autoimmune diseases. In vaccine development, a major aim is to induce strong, specific T-cell responses. This is achieved by targeting antigen to cell surface molecules on DCs that efficiently channel the antigen into endocytic compartments for loading onto MHC molecules and stimulation of T-cell responses. The most attractive cell surface receptors, expressed on DCs used as targets for antigen delivery for cancer and other diseases, are discussed.

scholarly journals Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
David W. Hawman ◽  
Kimberly Meade-White ◽  
Elaine Haddock ◽  
Rumi Habib ◽  
Dana Scott ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Severe Disease ◽  
Small Animal ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Type I ◽  
Crimean Congo Hemorrhagic Fever ◽  
Cell Responses

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying. IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

scholarly journals Signal 3 Cytokines as Modulators of Primary Immune Responses during Infections: The Interplay of Type I IFN and IL-12 in CD8 T Cell Responses

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40865 ◽  
Author(s):  
Selina Jessica Keppler ◽  
Kerstin Rosenits ◽  
Tamara Koegl ◽  
Smiljka Vucikuja ◽  
Peter Aichele
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Cell Responses

scholarly journals Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Loïc Vivien Bocard ◽  
Andrew Robert Kick ◽  
Corinne Hug ◽  
Heidi Erika Lisa Lischer ◽  
Tobias Käser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.

scholarly journals Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Yana Hackler ◽  
Frank Siebenhaar ◽  
Max Löhning ◽  
Marcus Maurer ◽  
Melba Muñoz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mast Cells ◽  
Immune Responses ◽  
Cytokine Production ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
Deficient Mice ◽  
Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

Activation of influenza virus–specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3520-3526 ◽  
Author(s):  
Jean-François Fonteneau ◽  
Michel Gilliet ◽  
Marie Larsson ◽  
Ida Dasilva ◽  
Christian Münz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Cell Responses ◽  
Adaptive Immune

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons (IFNs) upon exposure to enveloped viruses. However, their role in adaptive immune responses, such as the initiation of antiviral T-cell responses, is not known. In this study, we examined interactions between blood pDCs and influenza virus with special attention to the capacity of pDCs to activate influenza-specific T cells. pDCs were compared with CD11c+ DCs, the most potent antigen-presenting cells (APCs), for their capacity to activate T-cell responses. We found that like CD11c+ DCs, pDCs mature following exposure to influenza virus, express CCR7, and produce proinflammatory chemokines, but differ in that they produce type I IFN and are resistant to the cytopathic effect of the infection. After influenza virus exposure, both DC types exhibited an equivalent efficiency to expand anti–influenza virus cytotoxic T lymphocytes (CTLs) and T helper 1 (TH1) CD4+ T cells. Our results pinpoint a new role of pDCs in the induction of antiviral T-cell responses and suggest that these DCs play a prominent role in the adaptive immune response against viruses.

scholarly journals Immunodominance of Adenovirus-Derived CD8+ T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Dominik Schöne ◽  
Camilla Patrizia Hrycak ◽  
Sonja Windmann ◽  
Dennis Lapuente ◽  
Ulf Dittmer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Vaccine Development ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Content Type ◽  
Cell Responses

ABSTRACT Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8+ T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8+ T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL85–93. We show now that induction of GagL85–93-specific CD8+ T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL85–93 and the two Ad-derived epitopes DNA-binding protein418–426 (DBP418–426) and hexon486–494, we confirmed that Ad epitopes prevent induction of GagL85–93-specific CD8+ T cells. Interestingly, while DBP418–426 did not interfere with GagL85–93-specific CD8+ T cell induction, the H-2Dd-restricted hexon486–494 suppressed the CD8+ T cell response to the H-2Db-restricted GagL85–93 strongly in H-2b/d mice but not in H-2b/b mice. This finding indicates that competition occurs at the level of responding CD8+ T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL85–93-specific CD8+ T cell responses to epitope strings in the presence of hexon486–494. IL-2 codelivery did not restore GagL85–93 responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses. IMPORTANCE Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus, Plasmodium falciparum, or Mycobacterium tuberculosis. Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.

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