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 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.

scholarly journals 683 Type-I-interferon activates cross-dressed CD11b+conventional dendritic cells to enhance anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Ellen Duong ◽  
Timothy Fessenden ◽  
Emi Lutz ◽  
Teresa Dinter ◽  
Leon Yim ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Critical Role ◽  
T Cell Responses ◽  
T Cell Immunity ◽  
Type I ◽  
Cell Responses ◽  
Cell Immunity ◽  
Cross Dressing

BackgroundConventional dendritic cells (cDC) are critical mediators of protective anti-tumor CD8+ T-cell responses.1 Batf3-driven DC1 are the predominant cDC subset driving anti-tumor immunity due to their specialized ability to cross-present antigens for T-cell activation.2–4 However, the contribution of other tumor-infiltrating DC subsets such as CD11b+ DC2 to anti-tumor immunity remains poorly characterized. Recent studies suggest that under inflammation, DC subsets can exist in various functional states with differential impacts on their stimulatory potential.5–7 In this study, we sought to dissect the contributions of distinct DC states during a productive or dysfunctional anti-tumor immune response. A nuanced understanding of DC activation states in tumors and the signals that drive them carries therapeutic potential to modulate anti-tumor immunity and enhance immunotherapy responses.MethodsWe compared the DC infiltrate of a regressing tumor and a progressing tumor to study DC states. Flow immunophenotyping and RNA-sequencing was performed to profile the intratumoral DC compartment. Sorted DC subsets were co-cultured with T-cells ex vivo to evaluate their stimulatory capacity. Cross-dressing (in vivo/ex vivo) was assayed by staining for transfer of tumor-derived H-2b MHC complexes to MHC-mismatched or β2M-deficient DC.ResultsAnti-tumor CD8+ T-cell responses in Batf3-/- mice lacking DC1 were maintained in regressor tumors but not progressor tumors, suggesting DC1-independent anti-tumor immunity. Functional assays and RNA-sequencing of the intratumoral DC compartment of regressor tumors revealed a Zbtb46-dependent CD11b+ cDC activation state expressing an interferon-stimulated gene signature (ISG+ DC) that was critical for driving optimal anti-tumor CD8+ T-cell responses. Sorted ISG+ DC could activate CD8+ T-cells similar to DC1. Unlike cross-presenting DC1, however, ISG+ DC acquired antigens by cross-dressing with tumor-derived peptide-MHC, thereby bypassing the requirement for cross-presentation to initiate CD8+ T-cell-immunity. Interestingly, ISG+ DC were enriched in regressor tumors compared to progressor tumors, and this was attributable to constitutive tumor cell-intrinsic type-I-interferon (IFN-I) production in regressor tumors. Ablation of tumor cell-derived IFN-I in regressor tumors led to complete loss of anti-tumor T-cell responses in Batf3-/- mice. Conversely, addition of IFNβ to progressor tumors induced ISG+ DC and rescued anti-tumor T-cell responses in Batf3-/- mice.ConclusionsWe identified a novel IFN-I-induced activation state of CD11b+ cDC, called ISG+ DC, that was capable of driving anti-tumor CD8+ T cell immunity by cross-dressing with tumor-derived pMHC complexes in the absence of DC1. Engaging additional functional states of DC, such as ISG+ DC, will strengthen anti-tumor immunity and may improve immunotherapy responses.ReferencesMerad M, et al. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013;31:563–604Hildner K, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008;322(5904)1097–100.Broz ML, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 2014;26(5):638–52.Roberts EW, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in Melanoma. Cancer Cell 2016;30(2):324–336.Maier B, et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 2020;580(7802):257–262.Bosteels C, et al. Inflammatory Type 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection. Immunity 2020;52(6):1039–1056.e9.Zilionis R, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019;50(5):1317–1334.e10.

scholarly journals MHC class II invariant chain–adjuvanted viral vectored vaccines enhances T cell responses in humans

2020 ◽  
Vol 12 (548) ◽  
pp. eaaz7715
Author(s):  
Ilaria Esposito ◽  
Paola Cicconi ◽  
Anna Morena D’Alise ◽  
Anthony Brown ◽  
Marialuisa Esposito ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Critical Role ◽  
T Cell Responses ◽  
Class Ii ◽  
Effector Memory ◽  
Invariant Chain ◽  
Cell Responses

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II–associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

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 A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1909 ◽  
Author(s):  
Jie Chen ◽  
Hui Liu ◽  
Tiffany Jehng ◽  
Yanqing Li ◽  
Zhoushi Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Tumor Regression ◽  
Critical Role ◽  
T Cell Responses ◽  
The United States ◽  
Tumor Vaccines ◽  
Cell Responses

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in activating cellular and humoral immune responses. DC-based tumor vaccines targeting tumor-associated antigens (TAAs) have been extensively tested and demonstrated to be safe and potent in inducing anti-TAA immune responses in cancer patients. Sipuleucel-T (Provenge), a cancer vaccine of autologous DCs loaded with TAA, was approved by the United States Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer. Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Due to the overall limited clinical efficacy of tumor vaccines, there is a need to enhance their potency. PD-L1 is a key immune checkpoint molecule and is frequently overexpressed on tumor cells to evade antitumor immune destruction. Repeated administrations of PD-L1 or PD-1 antibodies have induced sustained tumor regression in a fraction of cancer patients. In this study, we tested whether vaccinations with DCs, loaded with a PD-L1 immunogen (PDL1-Vax), are able to induce anti-PD-L1 immune responses. We found that DCs loaded with PDL1-Vax induced anti-PD-L1 antibody and T cell responses in immunized mice and that PD-L1-specific CTLs had cytolytic activities against PD-L1+ tumor cells. We demonstrated that vaccination with PDL1-Vax DCs potently inhibited the growth of PD-L1+ tumor cells. In summary, this study demonstrates for the first time the principle and feasibility of DC vaccination (PDL1-Vax) to actively induce anti-PD-L1 antibody and T cell responses capable of inhibiting PD-L1+ tumor growth. This novel anti-PD-L1 vaccination strategy could be used for cancer treatment and prevention.

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 Critical role for Sec22b-dependent antigen cross-presentation in antitumor immunity

2017 ◽  
Vol 214 (8) ◽  
pp. 2231-2241 ◽  
Author(s):  
Andrés Alloatti ◽  
Derek C. Rookhuizen ◽  
Leonel Joannas ◽  
Jean-Marie Carpier ◽  
Salvador Iborra ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses

CD8+ T cells mediate antigen-specific immune responses that can induce rejection of solid tumors. In this process, dendritic cells (DCs) are thought to take up tumor antigens, which are processed into peptides and loaded onto MHC-I molecules, a process called “cross-presentation.” Neither the actual contribution of cross-presentation to antitumor immune responses nor the intracellular pathways involved in vivo are clearly established because of the lack of experimental tools to manipulate this process. To develop such tools, we generated mice bearing a conditional DC-specific mutation in the sec22b gene, a critical regulator of endoplasmic reticulum–phagosome traffic required for cross-presentation. DCs from these mice show impaired cross-presentation ex vivo and defective cross-priming of CD8+ T cell responses in vivo. These mice are also defective for antitumor immune responses and are resistant to treatment with anti–PD-1. We conclude that Sec22b-dependent cross-presentation in DCs is required to initiate CD8+ T cell responses to dead cells and to induce effective antitumor immune responses during anti–PD-1 treatment in mice.

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