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1.
EBioMedicine ; 72: 103610, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1514150

ABSTRACT

BACKGROUND: Recent studies have provided evidence of T cell reactivity to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in significant numbers of non-infected individuals, which has been attributed to cross-reactive CD4 memory T cells from previous exposure to seasonal coronaviruses. Less evidence of cross-reactive memory CD8 T cells has been documented to date. METHODS: We used the NetCTLPan neural network of the Epitope Database and Analysis Resource to select a series of 27 HLA-A*02:01 epitopes derived from the proteome of SARS-CoV-2. Their binding capacity was assessed by a HLA-A*02:01 stabilization assay and by quantifying their binding to HLA-A*02:01 monomers for the generation of tetramers. Their ability to stimulate and induce expansion of SARS-CoV-2 reactive CD8 T cells was measured by flow cytometry. The TCR repertoire of COVID convalescent and healthy unexposed donors was analysed using the MIRA database. FINDINGS: The HLA-A*02:01 epitopes tested were able to stabilise HLA molecules and induce activation of CD8 T cells of healthy unexposed donors. Our results, based on specific tetramer binding, provide evidence supporting the presence of frequent cross-reactive CD8 T cells to SARS-CoV-2 antigens in non-exposed individuals. Interestingly, the reactive cells were distributed into naïve, memory and effector subsets. INTERPRETATION: Our data are consistent with a significant proportion of the reactive CD8 T clones belonging to the public shared repertoire, readily available in absence of previous contact with closely related coronaviruses. Furthermore, we demonstrate the immunogenic capacity of long peptides carrying T cell epitopes, which can serve to isolate virus-specific T cell receptors among the ample repertoire of healthy unexposed subjects and could have application in COVID-19 immunotherapy. Limitations of our study are that it concentrated on one MHC I allele (HLA-A*02:01) and the low numbers of samples and epitopes tested. FUNDING: See the Acknowledgements section.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Computer Simulation , Cross Reactions , Humans , Immunotherapy , Receptors, Antigen, T-Cell
2.
PLoS One ; 16(11): e0258743, 2021.
Article in English | MEDLINE | ID: covidwho-1511818

ABSTRACT

BCG vaccination is known to induce innate immune memory, which confers protection against heterologous infections. However, the effect of BCG vaccination on the conventional adaptive immune cells subsets is not well characterized. We investigated the impact of BCG vaccination on the frequencies of T cell subsets and common gamma c (γc) cytokines in a group of healthy elderly individuals (age 60-80 years) at one month post vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrate that BCG vaccination induced enhanced frequencies of central (p<0.0001) and effector memory (p<0.0001) CD4+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001), stem cell memory (p = 0.0001) CD4+ T cells and regulatory T cells. In addition, BCG vaccination induced enhanced frequencies of central (p = 0.0008), effector (p<0.0001) and terminal effector memory (p<0.0001) CD8+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001) and stem cell memory (p = 0.0034) CD8+T cells. BCG vaccination also induced enhanced plasma levels of IL-7 (p<0.0001) and IL-15 (p = 0.0020) but diminished levels of IL-2 (p = 0.0033) and IL-21 (p = 0.0020). Thus, BCG vaccination was associated with enhanced memory T cell subsets as well as memory enhancing γc cytokines in elderly individuals, suggesting its ability to induce non-specific adaptive immune responses.


Subject(s)
BCG Vaccine/immunology , Cytokines/immunology , Immunologic Memory/immunology , Interleukin Receptor Common gamma Subunit/immunology , Aged , Aged, 80 and over , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Female , Humans , Interleukins/immunology , Male , Middle Aged , Mycobacterium tuberculosis/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Vaccination/methods
3.
Front Immunol ; 12: 741639, 2021.
Article in English | MEDLINE | ID: covidwho-1497078

ABSTRACT

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Adolescent , Adult , Child , Child, Preschool , Cohort Studies , Convalescence , Environmental Exposure , Family Characteristics , Female , Humans , Immunity, Cellular , Immunologic Memory , Infant , Male , Middle Aged , Young Adult
4.
J Virol ; 95(15): e0053021, 2021 07 12.
Article in English | MEDLINE | ID: covidwho-1486507

ABSTRACT

Elicitation of lung tissue-resident memory CD8 T cells (TRMs) is a goal of T cell-based vaccines against respiratory viral pathogens, such as influenza A virus (IAV). C-C chemokine receptor type 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 TRMs in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (TC1/TC17/TH1/TH17) IAV nucleoprotein-specific lung TRMs to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced TRM development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendritic cells (DCs), and monocyte-derived dendritic cells internalized and processed vaccine antigen in lungs. We found that basic leucine zipper ATF-like transcription factor 3 (BATF3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127hi, KLRG-1lo, OX40+ve CD62L+ve, and mucosally imprinted CD69+ve CD103+ve effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung TRMs induced by CCR2 deficiency was linked to dampened expression of T-bet but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1/T17 functional programming, parenchymal localization of CD8/CD4 effector and memory T cells, recall T cell responses, and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced TRMs. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens, including IAV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IMPORTANCE While antibody-based immunity to influenza A virus (IAV) is type and subtype specific, lung- and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of antiviral lung-resident memory T cells following intranasal vaccination. These findings suggest that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses, such as IAV and SARS-CoV-2.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal , Immunologic Memory , Influenza A virus/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Receptors, CCR2/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Influenza A virus/genetics , Influenza Vaccines/genetics , Influenza Vaccines/pharmacology , Lung/immunology , Mice , Mice, Knockout , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/prevention & control , Receptors, CCR2/genetics
5.
Front Immunol ; 12: 758154, 2021.
Article in English | MEDLINE | ID: covidwho-1477831

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has severely impacted daily life all over the world. Any measures to slow down the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease disease severity are highly requested. Recent studies have reported inverse correlations between plasma levels of vitamin D and susceptibility to SARS-CoV-2 infection and COVID-19 severity. Therefore, it has been proposed to supplement the general population with vitamin D to reduce the impact of COVID-19. However, by studying the course of COVID-19 and the immune response against SARS-CoV-2 in a family with a mutated, non-functional vitamin D receptor, we here demonstrate that vitamin D signaling was dispensable for mounting an efficient adaptive immune response against SARS-CoV-2 in this family. Although these observations might not directly be transferred to the general population, they question a central role of vitamin D in the generation of adaptive immunity against SARS-CoV-2.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Familial Hypophosphatemic Rickets/genetics , Receptors, Calcitriol/genetics , SARS-CoV-2/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , COVID-19/immunology , Familial Hypophosphatemic Rickets/immunology , Female , Humans , Immunologic Memory/immunology , Lymphocyte Count , Vitamin D/blood , Vitamin D/therapeutic use
6.
Front Immunol ; 12: 748097, 2021.
Article in English | MEDLINE | ID: covidwho-1477829

ABSTRACT

The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19/complications , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/blood , Asymptomatic Infections , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Female , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Humans , Immunocompromised Host/immunology , Immunoglobulin G/blood , Lymphocyte Activation/immunology , Male , Middle Aged
7.
Front Immunol ; 12: 735922, 2021.
Article in English | MEDLINE | ID: covidwho-1477823

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major public health issue. COVID-19 is considered an airway/multi-systemic disease, and demise has been associated with an uncontrolled immune response and a cytokine storm in response to the virus. However, the lung pathology, immune response, and tissue damage associated with COVID-19 demise are poorly described and understood due to safety concerns. Using post-mortem lung tissues from uninfected and COVID-19 deadly cases as well as an unbiased combined analysis of histology, multi-viral and host markers staining, correlative microscopy, confocal, and image analysis, we identified three distinct phenotypes of COVID-19-induced lung damage. First, a COVID-19-induced hemorrhage characterized by minimal immune infiltration and large thrombus; Second, a COVID-19-induced immune infiltration with excessive immune cell infiltration but no hemorrhagic events. The third phenotype correspond to the combination of the two previous ones. We observed the loss of alveolar wall integrity, detachment of lung tissue pieces, fibroblast proliferation, and extensive fibrosis in all three phenotypes. Although lung tissues studied were from lethal COVID-19, a strong immune response was observed in all cases analyzed with significant B cell and poor T cell infiltrations, suggesting an exhausted or compromised immune cellular response in these patients. Overall, our data show that SARS-CoV-2-induced lung damage is highly heterogeneous. These individual differences need to be considered to understand the acute and long-term COVID-19 consequences.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Lung Injury/pathology , Pulmonary Alveoli/pathology , Pulmonary Fibrosis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/pathology , Epithelial Cells/pathology , Female , Hemorrhage/pathology , Humans , Inflammation/pathology , Lung/pathology , Lung Injury/virology , Lymphopenia/pathology , Macrophage Activation/immunology , Macrophages/immunology , Male , Middle Aged , Myocytes, Smooth Muscle/pathology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/pathology
8.
Viruses ; 13(10)2021 10 13.
Article in English | MEDLINE | ID: covidwho-1470992

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the coronavirus disease 2019 (COVID-19) pandemic, severely affecting public health and the global economy. Adaptive immunity plays a crucial role in fighting against SARS-CoV-2 infection and directly influences the clinical outcomes of patients. Clinical studies have indicated that patients with severe COVID-19 exhibit delayed and weak adaptive immune responses; however, the mechanism by which SARS-CoV-2 impedes adaptive immunity remains unclear. Here, by using an in vitro cell line, we report that the SARS-CoV-2 spike protein significantly inhibits DNA damage repair, which is required for effective V(D)J recombination in adaptive immunity. Mechanistically, we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site. Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , DNA Repair/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , V(D)J Recombination/genetics , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , BRCA1 Protein/antagonists & inhibitors , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Cell Line , DNA Damage/genetics , HEK293 Cells , Humans , Immunity, Humoral/immunology , Immunosuppression , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology , Tumor Suppressor p53-Binding Protein 1/antagonists & inhibitors
9.
Proc Natl Acad Sci U S A ; 118(44)2021 11 02.
Article in English | MEDLINE | ID: covidwho-1470027

ABSTRACT

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 100 million infections and millions of deaths. Effective vaccines remain the best hope of curtailing SARS-CoV-2 transmission, morbidity, and mortality. The vaccines in current use require cold storage and sophisticated manufacturing capacity, which complicates their distribution, especially in less developed countries. We report the development of a candidate SARS-CoV-2 vaccine that is purely protein based and directly targets antigen-presenting cells. It consists of the SARS-CoV-2 Spike receptor-binding domain (SpikeRBD) fused to an alpaca-derived nanobody that recognizes class II major histocompatibility complex antigens (VHHMHCII). This vaccine elicits robust humoral and cellular immunity against SARS-CoV-2 and its variants. Both young and aged mice immunized with two doses of VHHMHCII-SpikeRBD elicit high-titer binding and neutralizing antibodies. Immunization also induces strong cellular immunity, including a robust CD8 T cell response. VHHMHCII-SpikeRBD is stable for at least 7 d at room temperature and can be lyophilized without loss of efficacy.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , COVID-19/immunology , COVID-19/prevention & control , Pandemics , SARS-CoV-2/immunology , Amino Acid Sequence , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Antigen-Presenting Cells/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , Camelids, New World/immunology , Female , Histocompatibility Antigens Class II/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Immunization, Secondary , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Pandemics/prevention & control , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , SARS-CoV-2/genetics , Single-Domain Antibodies/administration & dosage , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/administration & dosage , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
10.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1467778

ABSTRACT

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B-expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell-based vaccine designs for this infectious disease.


Subject(s)
B7-H1 Antigen/immunology , CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunity, Cellular , Receptors, CXCR3/immunology , Adult , COVID-19/mortality , COVID-19/pathology , Epitopes, T-Lymphocyte/immunology , Female , France/epidemiology , Humans , Immunologic Memory , Lymphocyte Activation , Male , SARS-CoV-2 , Survival Rate/trends
11.
Nat Commun ; 12(1): 5839, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454764

ABSTRACT

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). Here we show that the majority of PLWH with ART suppressed HIV viral load, mount a detectable adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleoprotein are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.


Subject(s)
HIV Infections/immunology , HIV Infections/virology , Immunity, Humoral , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , Aged , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Formation/immunology , Antigens, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cohort Studies , Female , Genome, Human , HIV Infections/blood , Humans , Interferon-gamma/metabolism , Male , Middle Aged , Phenotype , Species Specificity , Tissue Donors
12.
Front Immunol ; 12: 737406, 2021.
Article in English | MEDLINE | ID: covidwho-1450813

ABSTRACT

IL-7/IL-7R signaling is critical for development, maturation, maintenance and survival of many lymphocytes in the thymus and periphery. IL-7 has been used as immunotherapy in pre-clinical and clinical studies to treat cancer, HIV infection and sepsis. Here, we discuss the critical function of IL-7 in diagnosis, prognosis and treatment of COVID-19 patients. We also summarize a promising role of IL-7 as a vaccine adjuvant. It could potentially enhance the immune responses to vaccines especially against SARS-CoV-2 or other new vaccines.


Subject(s)
Adjuvants, Immunologic , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Interleukin-7/immunology , SARS-CoV-2/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Humans , Immunogenicity, Vaccine/immunology , Interleukin-7/metabolism , Receptors, Interleukin-7/metabolism
13.
J Immunol ; 207(10): 2399-2404, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1450887

ABSTRACT

Immunity to pulmonary infection typically requires elicitation of lung-resident T cells that subsequently confer protection against secondary infection. The presence of tissue-resident T cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent patients is unknown. Using a sublethal mouse model of coronavirus disease 2019, we determined if SARS-CoV-2 infection potentiated Ag-specific pulmonary resident CD4+ and CD8+ T cell responses and if these cells mediated protection against secondary infection. S protein-specific T cells were present in resident and circulating populations. However, M and N protein-specific T cells were detected only in the resident T cell pool. Using an adoptive transfer strategy, we found that T cells from SARS-CoV-2 immune animals did not protect naive mice. These data indicate that resident T cells are elicited by SARS-CoV-2 infection but are not sufficient for protective immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lung/immunology , SARS-CoV-2/physiology , Adoptive Transfer , Angiotensin-Converting Enzyme 2/genetics , Animals , Cells, Cultured , Disease Models, Animal , Disease Resistance , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Spike Glycoprotein, Coronavirus/immunology , T-Cell Antigen Receptor Specificity
15.
Front Immunol ; 12: 735125, 2021.
Article in English | MEDLINE | ID: covidwho-1441109

ABSTRACT

Background: The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection. Methods: A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. Results: We revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. Conclusions: Our findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immune System Diseases/immunology , SARS-CoV-2 , Adult , Aged , CD8 Antigens/immunology , Cytokines/immunology , Female , HLA-DR Antigens/immunology , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Young Adult
16.
Front Immunol ; 12: 730051, 2021.
Article in English | MEDLINE | ID: covidwho-1441107

ABSTRACT

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these "hot" concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Humans
17.
Immunity ; 54(9): 2133-2142.e3, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1433401

ABSTRACT

SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses on healthy SARS-CoV-2-naive and recovered individuals prior to and following mRNA prime and boost vaccination. Vaccination induced rapid antigen-specific CD4+ T cell responses in naive subjects after the first dose, whereas CD8+ T cell responses developed gradually and were variable in magnitude. Vaccine-induced Th1 and Tfh cell responses following the first dose correlated with post-boost CD8+ T cells and neutralizing antibodies, respectively. Integrated analysis revealed coordinated immune responses with distinct trajectories in SARS-CoV-2-naive and recovered individuals. Last, whereas booster vaccination improved T cell responses in SARS-CoV-2-naive subjects, the second dose had little effect in SARS-CoV-2-recovered individuals. These findings highlight the role of rapidly primed CD4+ T cells in coordinating responses to the second vaccine dose in SARS-CoV-2-naive individuals.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Th1 Cells/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunization, Secondary , Immunologic Memory , Lectins, C-Type/metabolism , Lymphocyte Activation , Male , Middle Aged , Peptides/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
18.
Immunology ; 163(3): 239-249, 2021 07.
Article in English | MEDLINE | ID: covidwho-1434725

ABSTRACT

Communication between stromal and immune cells is essential to maintain tissue homeostasis, mount an effective immune response and promote tissue repair. This 'crosstalk' occurs in both the steady state and following a variety of insults, for example, in response to local injury, at sites of infection or cancer. What do we mean by crosstalk between cells? Reciprocal activation and/or regulation occurs between immune and stromal cells, by direct cell contact and indirect mechanisms, including the release of soluble cytokines. Moving beyond cell-to-cell contact, this review investigates the complexity of 'cross-space' cellular communication. We highlight different examples of cellular communication by a variety of lung stromal and immune cells following tissue insults. This review examines how the 'geography of the lung microenvironment' is altered in various disease states; more specifically, we investigate how this influences lung epithelial cells and fibroblasts via their communication with immune cells and each other.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epithelial Cells/immunology , Fibroblasts/immunology , Lung/pathology , Stromal Cells/immunology , Animals , Cell Communication , Cellular Microenvironment , Humans , Immunity, Cellular
19.
Virus Res ; 305: 198579, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433887

ABSTRACT

The SARS-CoV2 mediated Covid-19 pandemic has impacted humankind at an unprecedented scale. While substantial research efforts have focused towards understanding the mechanisms of viral infection and developing vaccines/ therapeutics, factors affecting the susceptibility to SARS-CoV2 infection and manifestation of Covid-19 remain less explored. Given that the Human Leukocyte Antigen (HLA) system is known to vary among ethnic populations, it is likely to affect the recognition of the virus, and in turn, the susceptibility to Covid-19. To understand this, we used bioinformatic tools to probe all SARS-CoV2 peptides which could elicit T-cell response in humans. We also tried to answer the intriguing question of whether these potential epitopes were equally immunogenic across ethnicities, by studying the distribution of HLA alleles among different populations and their share of cognate epitopes. Results indicate that the immune recognition potential of SARS-CoV2 epitopes tend to vary between different ethnic groups. While the South Asians are likely to recognize higher number of CD8-specific epitopes, Europeans are likely to identify higher number of CD4-specific epitopes. We also hypothesize and provide clues that the newer mutations in SARS-CoV2 are unlikely to alter the T-cell mediated immunogenic responses among the studied ethnic populations. The work presented herein is expected to bolster our understanding of the pandemic, by providing insights into differential immunological response of ethnic populations to the virus as well as by gaging the possible effects of mutations in SARS-CoV2 on efficacy of potential epitope-based vaccines through evaluating ∼40,000 viral genomes.


Subject(s)
COVID-19/immunology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Ethnic Groups , Genome, Viral , HLA Antigens/immunology , SARS-CoV-2/immunology , Africa/epidemiology , Alleles , Amino Acid Sequence , Asia/epidemiology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/epidemiology , COVID-19/genetics , COVID-19/pathology , Computational Biology/methods , Disease Susceptibility , Epitopes, B-Lymphocyte/classification , Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/classification , Epitopes, T-Lymphocyte/genetics , Europe/epidemiology , HLA Antigens/classification , HLA Antigens/genetics , Humans , Middle East/epidemiology , Oceania/epidemiology , Principal Component Analysis , RNA, Viral/genetics , RNA, Viral/immunology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
20.
Front Immunol ; 12: 716084, 2021.
Article in English | MEDLINE | ID: covidwho-1430699

ABSTRACT

A binary model for the classification of chronic diseases has formerly been proposed. The model classifies chronic diseases as "high Treg" or "low Treg" diseases according to the extent of regulatory T cells (Treg) activity (frequency or function) observed. The present paper applies this model to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The model correctly predicts the efficacy or inefficacy of several immune-modulating drugs in the treatment of severe coronavirus disease 2019 (COVID-19) disease. It also correctly predicts the class of pathogens mostly associated with SARS-CoV-2 infection. The clinical implications are the following: (a) any search for new immune-modulating drugs for the treatment of COVID-19 should exclude candidates that do not induce "high Treg" immune reaction or those that do not spare CD8+ T cells; (b) immune-modulating drugs, which are effective against SARS-CoV-2, may not be effective against any variant of the virus that does not induce "low Treg" reaction; (c) any immune-modulating drug, which is effective in treating COVID-19, will also alleviate most coinfections; and (d) severe COVID-19 patients should avoid contact with carriers of "low Treg" pathogens.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , Immunomodulation/drug effects , T-Lymphocytes, Regulatory/immunology , Adrenal Cortex Hormones/therapeutic use , COVID-19/immunology , Chronic Disease/classification , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Sirolimus/therapeutic use
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