scholarly journals Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Raphaëlle Riou ◽  
Céline Bressollette-Bodin ◽  
David Boutoille ◽  
Katia Gagne ◽  
Audrey Rodallec ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Cytokine Production ◽  
Lymphocyte Activation ◽  
Adaptive Immune Responses ◽  
Host Immune Responses ◽  
Adaptive Immune ◽  
Cell Compartments

ABSTRACT Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+ NK cells, CD16+ Vδ2(−) γδ T cells, and conventional HCMV-specific CD8+ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals. IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

scholarly journals Mast cells and γδ T cells are largely dispensable for adaptive immune responses after laser-mediated epicutaneous immunization

Vaccine ◽  
2020 ◽  
Vol 38 (5) ◽  
pp. 1015-1024
Author(s):  
Isabella A. Joubert ◽  
Daniel Kovacs ◽  
Sandra Scheiblhofer ◽  
Petra Winter ◽  
Evgeniia Korotchenko ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Immune Responses ◽  
Γδ T Cells ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

CD154:CD40 Co-Stimulatory Blockade: A Novel Approach To Prevent Sensitization to Donor Alloantigens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1273-1273
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Suzanne T. Ildstad
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Germinal Center ◽  
Cell Activation ◽  
Cell Tolerance ◽  
B Cell Activation ◽  
B Cell Tolerance ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

Abstract Introduction: Recipient sensitization is one of the most critical problems facing clinical transplantation. Allosensitized recipients often rapidly reject vascularized solid organ grafts as a result of preformed anti-donor antibody. Similarly, bone marrow transplantation for sickle cell disease and thalassemia is limited by sensitization from transfusion. A method to prevent sensitization would have a significant impact on transplant outcomes. Until recently, T cells were believed to be the primary effector cell in the induction of adaptive immune responses. We recently found that humoral immunity provides a dominant barrier in allosensitization to MHC antigens. B cell activation occurs through T-cell-dependent responses via signaling from the co-stimulatory molecule CD154 (on T cells) to its ligand CD40 (on B cells). Here, we examined whether blocking the costimulatory interaction between T and B cells during exposure to alloantigen would prevent allosensitization. Materials and Methods: Mice deficient for CD154 molecule (CD154−/ −, H-2b), α β-TCR+ T cells (TCRβ −/ −, H-2b); or wild type B6 (H-2b) mice received allogeneic BALB/c (H-2d) skin grafts (SG) on day 0. Some B6 mice were also treated with anti-CD154 (day0 and day+3) and/or anti-α β-TCR mAb (day-3) peritransplant. Antibodies were detected by flow cytometry cross-match (FCM) assay and reported as mean fluorescence intensity (MFI). Results: CD154−/ − mice rejected primary BALB/c SG with a time course similar to normal B6 controls (12.4 ± 2.1 vs. 12.7 ± 2.4 days). TCRβ −/ − mice accepted SG permanently (>120 days). Notably, anti-donor antibody was not generated in either the CD154−/ − or TCRβ −/ − mice (MFI: 4.1 ± 0.1 and 4.2 ± 0.4) after SG compared with Ab in naïve serum (3.0±0.2). Sensitized B6 mice had significantly higher antibody titers (106.8 ± 35.1) 4 weeks after SG rejection. A second SG transplanted 5 to 7 weeks after the first graft was rejected at an accelerated rate (9.0 ± 0.8 days, P < 0.05) in the CD154−/ − mice, but no anti-donor MHC antibody was produced. Second grafts placed on TCRβ −/ − mice were accepted, as were the primary SG. In normal B6 recipients pretreated with anti-CD154 or anti-α β-TCR alone, SG survival was not significantly prolonged. The Ab titers were only slightly higher in mice treated with anti-CD154 (5.9±3.4; P>0.05) than in naïve mice, and significantly higher in mice treated with mAb anti-α β-TCR (45.1±25.6; P=0.03). The combined treatment with both mAbs resulted in complete abrogation of Ab production (4.2±0.9) and 70% of skin grafts survived >100 days. Germinal center formation, reflective of B cell activation, was completely disrupted in mice treated with anti-CD154 alone or combined with anti-α β-TCR. Conclusion: These results suggest that the CD40/CD154 co-stimulatory pathway is critically important in B cell activation to generate alloantibody. Notably, blocking molecular interactions between CD40/CD154 abrogated the generation of antibody and blocked germinal center formation, inducing B cell tolerance. The additional removal of recipient T cells in the context of co-stimulatory blockade resulted in the induction of T as well as B cell tolerance. These findings are the first demonstration that sensitization can be prevented through blockade of co-stimulatory interactions in the generation of adaptive immune responses and could have a significant impact on management of sensitized recipients in the clinic.

scholarly journals Early IL-17 Production by Intrahepatic T Cells Is Important for Adaptive Immune Responses in Viral Hepatitis

2012 ◽  
Vol 190 (2) ◽  
pp. 621-629 ◽  
Author(s):  
Lifei Hou ◽  
Zuliang Jie ◽  
Mayura Desai ◽  
Yuejin Liang ◽  
Lynn Soong ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Viral Hepatitis ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

scholarly journals Comparison of intestinal APC subsets from homeostatic and immunostimulatory environments

2021 ◽  
Author(s):  
◽  
Kerry Hilligan
Keyword(s):  
T Cells ◽  
Food Allergy ◽  
Immune Responses ◽  
Oral Administration ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Adaptive Immune ◽  
Inflammatory Bowel

<p>Antigen presenting cells (APC) including dendritic cells (DC) play a key role in the initiation and direction of adaptive immune responses. Acting as sentinels in the tissue, DC sample antigen and traffic to the local lymph node where they present antigen to naïve T cells. The signals DC provide to naïve T cells determines the functional fate of the T cell and therefore, the type of immune response generated. At mucosal sites, such as the intestine, immune responses need to be carefully regulated due to the high antigenic load. For this reason, intestinal immune cells are highly specialised to prevent immune activation to innocuous antigens while still holding the capacity to induce potent responses to pathogenic microbes and helminths. Oral administration of antigen is associated with tolerance and the generation of FoxP3+ regulatory T cells (Tregs). Specialised lamina propria (LP) resident APC are required for the initiation of Treg differentiation in the mesenteric lymph nodes (MLN) through production of chemical mediators such as retinoic acid (RA). Ablation of these populations or restricted trafficking prevents the development of Tregs in mouse models thus supporting the essential role of APC in maintaining intestinal homeostasis. During infection, APC promote the induction of adaptive immune responses which neutralise threats. However, the APC subsets involved in this are not well defined. Pathologies such as food allergy and inflammatory bowel disease are thought to arise due to the development of aberrant immune responses. Food allergy can be modelled in mice using the mucosal adjuvant cholera toxin (CT) which has been shown to drive immunity to co-delivered antigens and is associated with the generation of IL-4 producing T helper 2 cells. Understanding the APC subsets involved in the initiation of intestinal immune responses could help in the development of targeted therapies for inflammatory bowel conditions. In this thesis, I show that oral administration of CT is followed by the appearance of a novel phenotype of DC in the intestinal LP and MLN. These DC differ functionally from DC at steady-state and may contribute to the generation of IL-4 producing T cells observed in the LP, MLN and spleen following oral administration of CT.</p>

scholarly journals 62: Sensing and Alarm Function of Mucosal Memory CD8 T Cells Trigger Innate and Adaptive Immune Responses

2015 ◽  
Vol 143 (suppl_1) ◽  
pp. A034-A034 ◽  
Author(s):  
Jason M. Schenkel ◽  
Kathryn A. Fraser ◽  
Lalit K. Beura ◽  
Kristen E. Pauken ◽  
David Masopust ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Adaptive Immune Responses ◽  
Memory Cd8 T Cells ◽  
Adaptive Immune

scholarly journals Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo

2004 ◽  
Vol 78 (11) ◽  
pp. 5966-5972 ◽  
Author(s):  
Daniel A. Muruve ◽  
Matthew J. Cotter ◽  
Anne K. Zaiss ◽  
Lindsay R. White ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Second Phase ◽  
Liver Inflammation ◽  
Adaptive Immune Responses ◽  
Necrosis Factor Alpha ◽  
Host Immune Responses ◽  
Animal Models Of Disease ◽  
Adaptive Immune

ABSTRACT Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.

scholarly journals CD4+ T Cells and Toll-Like Receptors Recognize Salmonella Antigens Expressed in Bacterial Surface Organelles

2005 ◽  
Vol 73 (3) ◽  
pp. 1350-1356 ◽  
Author(s):  
Molly A. Bergman ◽  
Lisa A. Cummings ◽  
Sara L. Rassoulian Barrett ◽  
Kelly D. Smith ◽  
J. Cano Lara ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Membrane Vesicles ◽  
Surface Modifications ◽  
Immune Recognition ◽  
Toll Like Receptors ◽  
Bacterial Surface ◽  
Host Immune Responses ◽  
Adaptive Immune ◽  
Host Tissues

ABSTRACT A better understanding of immunity to infection is revealed from the characteristics of microbial ligands recognized by host immune responses. Murine infection with the intracellular bacterium Salmonella generates CD4+ T cells that specifically recognize Salmonella proteins expressed in bacterial surface organelles such as flagella and membrane vesicles. These natural Salmonella antigens are also ligands for Toll-like receptors (TLRs) or avidly associated with TLR ligands such as lipopolysaccharide (LPS). PhoP/PhoQ, a regulon controlling Salmonella virulence and remodeling of LPS to resist innate immunity, coordinately represses production of surface-exposed antigens recognized by CD4+ T cells and TLRs. These data suggest that genetically coordinated surface modifications may provide a growth advantage for Salmonella in host tissues by limiting both innate and adaptive immune recognition.

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