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The rapidly spreading severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron variant contains more than 30 mutations that mediate escape from antibody responses elicited by prior infection or current vaccines. Fortunately, T‐cell responses are highly conserved in most individuals, but the impacts of mutations are not clear. Here, we showed that the T‐cell responses of individuals who underwent booster vaccination with CoronaVac were largely protective against the SARS‐CoV‐2 Omicron spike protein. To specifically estimate the impact of Omicron mutations on vaccinated participants, 16 peptides derived from the spike protein of the ancestral virus or Omicron strain with mutations were used to stimulate peripheral blood mononuclear cells (PBMCs) from the volunteers. Compared with the administration of two doses of vaccine, booster vaccination substantially enhanced T‐cell activation in response to both the ancestral and Omicron epitopes, although the enhancement was slightly weakened by the Omicron mutations. Then, the peptides derived from these spike proteins were used separately to stimulate PBMCs. Interestingly, compared with the ancestral peptides, only the peptides with the G339D or N440K mutation were detected to significantly destabilize the T‐cell response. Although more participants need to be evaluated to confirm this conclusion, our study nonetheless estimates the impacts of mutations on T‐cell responses to the SARS‐CoV‐2 Omicron variant. [ABSTRACT FROM AUTHOR]

The Japanese encephalitis (JE) live‐attenuated vaccine SA14‐14‐2 and the chimeric vaccine IMOJEV (JE‐CV) are two kinds of vaccines available for use worldwide. JE‐CV was previously known as ChimeriVax‐JE, that consists of yellow fever vaccine 17D (YFV‐17D) from which the structural genes (prM/E) have been replaced with those of SA14‐14‐2. This study aimed to investigate the neutralizing antibody, protection efficacy, and specific T‐cell response elicited by both vaccines in mice. The neutralizing antibodies produced by JE‐CV were slightly lower than those produced by SA14‐14‐2, but the protection conferred by JE‐CV was considerably lower in the low vaccine dose immunization group. Furthermore, the JE‐CV did not induce a specific T‐cell response against JEV NS3, while it did induce a potent antigen‐specific T‐cell response against the viral backbone vaccine YFV. In conclusion, this study is the first detailed investigation of the cellular immune response to the two vaccines. Enzyme‐linked immunospot (ELISPOT) and flow staining suggest a more potent specific T‐cell response against the JEV antigen was elicited in mice immunized with SA14‐14‐2 but not JE‐CV. Using heterologous flaviviruses as a live‐attenuated vaccine backbone may unlikely generate an optimal T‐cell response against the vaccine strain virus and might affect the protective efficacy. [ABSTRACT FROM AUTHOR]

Mycolic acids (MAs) are highly hydrophobic long-chain α-alkyl β-hydroxy fatty acids present in the cell wall of Mycobacterium tuberculosis ( Mtb) as a complex mixture of molecules with a common general structure but with variable functional groups in the meromycolate chain. In this study, we addressed the relationship between the MA molecular structure and their contribution to the development of T-cell immune responses. Hereto, we used the model antigen ovalbumin and single synthetic MAs, differing in oxygenation class and cis versus trans proximal cyclopropane configuration, as immune stimulatory agents. Subcutaneous delivery of liposome-formulated MAs with a proximal cis cyclopropane elicited antigen-specific Th1 and cytotoxic T-cell immune responses, whereas intratracheal immunization elicited pulmonary Th17 responses. These immune stimulatory activities depended not only on the cis versus trans proximal cyclopropane configuration but also on the MA oxygenation class. Our study thus shows that both the presence and nature of the functional groups in the meromycolate chain affect the immune stimulatory adjuvant activity of Mtb mycolates and suggests that Mtb bacilli may impact on the host protective immune response by modulating the cis versus trans stereochemistry of its mycolates as well as by altering the oxygenation class of the meromycolate functional group. [ABSTRACT FROM AUTHOR]

FoxP3+ Treg cells and anergic T cells are the two regulatory phenotypes of T-cell responses associated with helminth infection. Here, we examine the T-cell responses in mice during Fasciola hepatica infection, and to its tegumental coat antigens (FhTeg) that are shed from the fluke every 2-3 h. FhTeg comprises a rich source of glycoproteins, mainly oligomannose N-glycans that bind to mannose receptor. This study demonstrated a novel mechanism for the T-cell unresponsiveness observed during F. hepatica infection and after injection with FhTeg. Markers of T-cell anergy, such as GRAIL, EGR2, ICOS, and ITCH, are enhanced amongst CD4+ T-cell populations during infection and following FhTeg injection. This is characterized by a lack of cytokine responses and reduced proliferative activity, which can be reversed with the addition of IL-2. FhTeg-activated dendritic cells (DCs) suppress T cells in vitro as measured by enhanced GRAIL and CTLA4 by RNA and suppressed cytokine expression in anti-CD3 stimulated CD4+ T cells. FhTeg-treated DCs have enhanced MR expression, which is critical for DC-CD4+ T-cell communication. Taken together, this study presents markers of anergy in a mouse model of F. hepatica infection, and improves our understanding of host-pathogen interactions and how helminths modulate host immunity. [ABSTRACT FROM AUTHOR]

Background An autologous vaccine of apoptotic tumor cells (ATCs) and dendritic cells (DCs) was administered to patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) to study safety and feasibility. Methods Autologous DCs were generated from monocytes, loaded with ATCs, and delivered intranodally. Delayed-type hypersensitivity (DTH) and immunological endpoints were measured prevaccination and postvaccination. Clinical follow-up was required. Results Tumors obtained from 30 patients yielded 2 × 106 to 2 × 108 tumor cells. Only 19 of 30 (63%) were sterile. Ten of 30 patients (33%) had ≥1 × 107 sterile tumor cells required for vaccine production. Eight of 10 patients had positive recall DTH. Five of 10 patients were leukapheresed to generate DCs. Four of 5 patients were vaccinated. ATC-reactive T cells were detected in 3 of 4 patients. All 4 patients survived >5 years. The trial failed to enroll the projected 12 patients and was terminated. Conclusion This vaccine was safe and immunogenic but feasible only in patients with HNSCC with positive prevaccine DTH and ≥1 × 107 sterile tumor cells. All vaccinated patients were long-term disease-free survivors. © 2015 Wiley Periodicals, Inc. Head Neck 38: E494-E501, 2016 [ABSTRACT FROM AUTHOR]

Interactions between ICOS and ICOS ligand (ICOSL) are essential for the development of T follicular helper (Tfh) cells and thus the formation and maintenance of GC reactions. Given the conflicting reports on the requirement of other CD4+ T-cell populations for ICOS signals, we have employed a range of in vivo approaches to dissect requirements for ICOS signals in mice during an endogenous CD4+ T-cell response and contrasted this with CD28 signals. Genetic absence of ICOSL only modestly reduced the total number of antigen-specific CD4+ T cells at the peak of the primary response, but resulted in a severely diminished number of both T central memory and T effector memory cells. Treatment with blocking anti-ICOS mAb during the primary response recapitulated these effects and caused a more substantial reduction than blocking CD28 signals with CTLA4Ig. During the memory phase of the response further signals through ICOS or CD28 were not required for survival. However, upon secondary challenge only Tfh cell expansion remained heavily ICOS-dependent, while CD28 signals were required for optimal expansion of all subsets. These data demonstrate the importance of ICOS signals specifically for memory CD4+ T-cell formation, while highlighting the potential of therapeutically targeting this pathway. [ABSTRACT FROM AUTHOR]

Allergic sensitization is initiated by allergen-specific Th2-cell responses. Data on early allergen-specific T-cell responses in allergic children are scarce. We hypothesized that allergen-specific Th2-cell responses can be detected preceding sensitization. Therefore, peripheral blood mononuclear cells ( PBMC) of nonsensitized, 'not-yet' sensitized or sensitized children were cultured with highly purified allergens. Cytokine levels in supernatant were determined using multiplex assay and GATA3 expression by flow cytometry. PBMC of sensitized children aged 3 and 5 years showed higher production of IL4, IL5 and IL13 and higher expression of GATA3 in response to purified allergens compared to nonsensitized children. PBMC of children that were 'not-yet' sensitized already showed higher levels of IL5 and IL13 and higher GATA3 expression at age 3 years. This shows that allergen-specific in vitro Th2 responses precede the detection of allergen-specific IgE, which can provide a window of opportunity for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Lymphoid-tissue dendritic cells ( DCs) are short-lived and need to be continuously replenished from bone marrow-derived DC progenitor cells. Fms-related tyrosine kinase 3 is expressed during cellular development from hematopoietic progenitors to lymphoid-tissue DCs. Fms-related tyrosine kinase 3 ligand ( Flt3L) is an essential, nonredundant cytokine for DC progenitor to lymphoid tissue DC differentiation and maintenance. However, which cells contribute to Flt3L production and how Flt3L cytokine levels are regulated in steady state and during immune reactions remains to be determined. Here we demonstrate that besides nonhematopoietic cells, WT T cells produce Flt3 L and contribute to the generation of both classical DCs (c DCs) and plasmacytoid DCs in Flt3 L−/− mice. Upon stimulation in vitro, CD4+ T cells produce more Flt3 L than CD8+ T cells. Moreover, in vivo stimulation of naïve OT- II CD4+ T cells with OVA leads to increase of pre-c DCs and c DCs in draining lymph nodes of Flt3 L−/− mice in a partially Flt3 L-dependent manner. Thus, Flt3 L-mediated lymphoid tissue DC homeostasis is regulated by steady-state T cells as well as by proliferative T cells, fostering local development of lymphoid organ resident DCs. [ABSTRACT FROM AUTHOR]

T-cell responses are initiated within secondary lymphoid organs, and effector T-cells are released into the circulation where they home to inflamed tissues and mediate protective immune responses. Within non-lymphoid tissues, the types of cellular interactions and the dynamics that lead to clearance of infections are still relatively poorly understood. Here I review how imaging of effector T-cells within tissues has contributed to our understanding of immune responses, and examine some of the remaining questions that may benefit from in vivo imaging to reveal the intricacies of how immune cells function. A detailed understanding of the dynamics of T-cell responses within non-lymphoid tissues is important for the rational design of targeted therapies that influence key steps in disease progression. [ABSTRACT FROM AUTHOR]

. A new hepatitis B virus (HBV) protein, hepatitis B splice-generated protein (HBSP), has been detected in liver biopsy specimens from patients with chronic active hepatitis. The aim of this study was to characterize the phenotype and functions of peripheral HBSP-specific T cells and to determine whether these T-cell responses may be implicated in liver damage or viral control. Two groups of patients were studied: HBV-infected patients with chronic active hepatitis and HBV-infected patients who were inactive carriers of hepatitis B surface antigen. HBSP-specific T-cell responses were analysed ex vivo and after in vitro stimulation of peripheral blood mononuclear cells. Soluble cytokines and chemokines were analysed in sera and in cell culture supernatants. Few HBSP- or capsid-specific T-cell responses were detected in patients with chronic active hepatitis whereas frequency of HBV-specific T cells was significantly higher in inactive carrier patients. HBSP activated CD8+ and CD4+ T cells that recognized multiple epitopes and secreted inflammatory cytokines. The IL-12 level was significantly lower in sera from asymptomatic carrier patients compared to patients with chronic active hepatitis. IL-12 and IP-10 levels in the sera were significantly and independently correlated with both alanine amino transferase and HBV DNA levels. Our results show that the HBSP protein activates cellular immune responses in HBV-infected patients but has probably no prominent role in liver damage. The pattern of cytokines and chemokines in sera was linked to HBV viral load and was consistent with the level of inflammation during chronic hepatitis. [ABSTRACT FROM AUTHOR]

The 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) interfere with the mevalonate pathway. While initially developed for their lipid-lowering properties, statins have been extensively investigated with respect to their impact on autoantigen and alloantigen driven immune responses. Mechanistically it was shown that statins modify immune responses on several levels, including effects on dendritic cells, endothelial cells, macrophages, B cells and T cells. Several lines of evidence suggest that statins act in a disease-specific manner and are not effective in each immune disorder. This review discusses possible modes of action of statins in modulating immunity towards autoantigens and alloantigens. [ABSTRACT FROM AUTHOR]

Therapy with interferon-β (IFN-β) has well-established clinical effects in multiple sclerosis (MS), albeit the immunomodulatory mechanisms are not fully understood. We assessed the prevalence and functional capacity of CD4+ and CD8+ T cells in healthy donors, and in untreated and IFN-β-treated MS patients, in response to myelin oligodendrocyte glycoprotein (MOG). The proportion of CD45RO+ memory T cells was higher in MS patients than in healthy donors, but returned to normal values upon therapy with IFN-β. While CD45RO+ CD4+ T cells from all three groups responded to MOG in vitro, untreated patients showed augmented proliferative responses compared to healthy individuals and IFN-β treatment reduced this elevated reactivity back to the values observed in healthy donors. Similarly, the response of CD45RO+ CD8+ T cells to MOG was strongest in untreated patients and decreased to normal values upon immunotherapy. Overall, the frequency of peripheral CD45RO+ memory T cells ex vivo correlated with the strength of the cellular in vitro response to MOG in untreated patients but not in healthy donors or IFN-β-treated patients. Compared with healthy individuals, responding CD4+ and CD8+ cells were skewed towards a type 1 cytokine phenotype in untreated patients, but towards a type 2 phenotype under IFN-β therapy. Our data suggest that the beneficial effect of IFN-β in MS might be the result of the suppression or depletion of autoreactive, pro-inflammatory memory T cells in the periphery. Assessment of T-cell subsets and their reactivity to MOG may represent an important diagnostic tool for monitoring successful immunotherapy in MS. [ABSTRACT FROM AUTHOR]

To define the level of pathogen-specific immune reconstitution persisting over 3 to 5 years of highly active antiretroviral therapy (HAART) in HIV-infected patients who began therapy with CD4 T-cell counts below 50 cells/μL.Cytomegalovirus (CMV)-specific T-cell responses were analysed in adult HIV-1-infected patients with nadir CD4 T-cell counts below 50 cells/μL before HAART. CMV-specific CD4 T-cell responses were measured by interferon-γ enzyme-linked immunospot assay (ELISpot assay), lymphoproliferation and interferon-γ levels in cell culture supernatants.CD4 T-cell responses to CMV were low in untreated patients and remained low during the first year on HAART, but increased progressively to levels similar to those found in HIV-seronegative CMV-seropositive controls at 3 years. Responses then declined markedly and at 5 years were lower than controls. This could not be explained by changes in CD4 or CD8 T-cell counts or plasma HIV RNA levels. Interferon-γ and interleukin-5 responses to a mitogen were maintained or elevated.CMV-specific CD4 T-cell responses were found to decline after 3–5 years on HAART and may provide inadequate long-term protection against CMV disease in patients who are severely immunodeficient prior to treatment. [ABSTRACT FROM AUTHOR]

Focuses on the importance of infections in exacerbation of asthma. Relation to viral infections; Attempts to modify the course of the disease by immunologic intervention in bacterial infections; Clinical documentation of the effect of bacterial vaccines in asthma; Relation between infections and the development of Th-cell cytokine profiles.

To investigate mechanisms of stem cell graft rejection we studied the allo-stimulatory potential of G-CSF mobilized peripheral blood progenitor cells (PBPC). CD34+ cells were purified (> 95%) in a two-step procedure using immunoaffinity columns for CD34 selection and T-depletion. The capacity of CD34+ cells to stimulate allogeneic T-cell responses was compared with other cells from the same individual. CD34+ cells induced potent proliferative responses at stimulator:responder ratios of 1:20, but were approximately 50-fold less efficient compared to dendritic cells. Furthermore, CD34+ cells primed responses from partially matched allogeneic T cells in bulk cultures. Dual-colour flow cytometry showed that the co-stimulatory molecules B7.1, CD40 and ICAM-1 were absent on resting CD34-positive progenitor cells, but were induced during incubation with allogeneic lymphocytes due to a cytokine-mediated effect. Up-regulation of accessory molecules on CD34+ cells was reproduced by incubation with interferon-γ or GM-CSF which enhanced the allo-stimulatory activity of CD34+ cells. Blocking studies with inhibitory antibodies suggested co-stimulatory functions for B7.2, ICAM-3, CD40 and LFA-3. CD34+ cells were more efficient in inducing allogeneic T-cell responses when compared to the unprocessed leukapheresis products. The reduced allo-stimulatory ability of G-CSF mobilized PBPC could be explained by the presence of CD3+4+ and CD3+8+ lymphocytes with suppressor activity. We conclude that current methods of stem cell selection for transplantation do not avoid allo-sensitization of the recipient and that further graft manipulation with add-back of lymphocytes or selection of subsets of CD34+ cells with reduced allo-stimulatory ability may reduce graft rejection. [ABSTRACT FROM AUTHOR]

Objectives: Infections are a major cause of mortality after allogeneic haemopoietic stem cell transplantation (alloHSCT), and immune recovery is necessary for prevention. Novel transplant procedures have changed the epidemiology of infections but contemporary data on functional immune recovery are limited. In this pilot study, we aimed to measure immune recovery in the current era of alloHSCT. Methods: Twenty, 13, 11, 9 and 9 alloHSCT recipients had blood collected at baseline (time of conditioning) and 3‐, 6‐, 9‐, and 12‐months post‐alloHSCT, respectively. Clinical data were collected, and immune recovery was measured using immunophenotyping, lymphocyte proliferation, cytokine analysis and antibody isotyping. Results: Median absolute T‐ and B‐cell counts were below normal from baseline until 9‐ to 12‐months post‐alloHSCT. Median absolute CD4+ T‐cell counts recovered at 12‐months post‐alloHSCT. Positive proliferative responses to Aspergillus, cytomegalovirus (CMV), Epstein‐Barr virus (EBV), influenza and tetanus antigens were detected from 9 months. IL‐6 was the most abundant cytokine in cell cultures. In cultures stimulated with CMV, EBV, influenza and tetanus peptides, the CD4+ T‐cell count correlated with IL‐1β (P = 0.045) and CD8+ T‐cell count with IFNγ (P = 0.013) and IL‐1β (P = 0.012). The NK‐cell count correlated with IL‐1β (P = 0.02) and IL‐17a (P = 0.03). Median serum levels of IgG1, IgG2 and IgG3 were normal while IgG4 and IgA were below normal range throughout follow‐up. Conclusions: This pilot study demonstrates that immune recovery can be measured using CD4+ T‐cell counts, in vitro antigen stimulation and selected cytokines (IFNγ, IL‐1β, IL‐4, IL‐6, IL‐17, IL‐21, IL‐31) in alloHSCT recipients. While larger studies are required, monitoring immune recovery may have utility in predicting infection risk post‐alloHSCT. Infection is a major problem in allogeneic stem cell transplant recipients. Immune‐based risk stratification is required to guide the duration of anti‐microbial prophylaxis administration and timing of re‐vaccination. This proof of concept study demonstrates that immune recovery can be measured using CD4+ T‐cell counts, pathogen specific immune responses and selected cytokines (IFN‐gamma, IL‐1‐beta, IL‐4, IL‐6, IL‐17, IL‐21, IL‐31). Immune parameters measured may have utility in infection‐risk stratification and provides a framework for larger cohort studies. [ABSTRACT FROM AUTHOR]