scholarly journals Integrated longitudinal immunophenotypic, transcriptional and repertoire analyses delineate immune responses in COVID-19 patients

2021 ◽  
Vol 6 (62) ◽  
pp. eabg5021
Author(s):  
Samuele Notarbartolo ◽  
Valeria Ranzani ◽  
Alessandra Bandera ◽  
Paola Gruarin ◽  
Valeria Bevilacqua ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Post Infection ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Effector Memory ◽  
Type I ◽  
Effector Cells ◽  
Mild Disease ◽  
Mait Cells

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.

scholarly journals Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection

2020 ◽  
Author(s):  
Jessica B. Graham ◽  
Jessica L. Swarts ◽  
Sarah R. Leist ◽  
Alexandra Schäfer ◽  
Vineet D. Menachery ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcomes ◽  
Severe Disease ◽  
Collaborative Cross ◽  
Viral Control ◽  
Major Barrier ◽  
Mild Disease ◽  
Immune Correlates ◽  
Wide Range

AbstractThe COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans, from asymptomatic or mild disease to severe disease that can require mechanical ventilation. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from indiviuals that go on to become infected with SARS-CoV-2. Here, we utilized data from a screen of genetically diverse mice from the Collaborative Cross (CC) infected with SARS-CoV to determine whether circulating baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Further, early control of virus in the lung correlates with an increased abundance of activated CD4 and CD8 T cells and regulatory T cells prior to infections across strains. A basal propensity of T cells to express IFNg and IL17 over TNFa also correlated with early viral control. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. While future studies of human samples prior to infection with SARS-CoV-2 are required, our studies in mice with SARS-CoV serve as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.SummaryWe used a screen of genetically diverse mice from the Collaborative Cross infected with mouse-adapted SARS-CoV in combination with comprehensive pre-infection immunophenotyping to identify baseline circulating immune correlates of severe virologic and clinical outcomes upon SARS-CoV infection.

scholarly journals Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c

2013 ◽  
Vol 81 (11) ◽  
pp. 4171-4181 ◽  
Author(s):  
Laura A. Cooney ◽  
Megha Gupta ◽  
Sunil Thomas ◽  
Sebastian Mikolajczak ◽  
Kimberly Y. Choi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Plasmodium Yoelii ◽  
T Cell Response ◽  
Parasite Development ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Ifn Γ

ABSTRACTVaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodentPlasmodium yoeliimodel. Protection is dependent on CD8+T cells, involves perforin and gamma interferon (IFN-γ), and is correlated with the expansion of effector memory CD8+T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8+T cell phenotype and demonstrated significant upregulation of CD11c on CD3+CD8b+T cells in the liver, spleen, and peripheral blood. CD11c+CD8+T cells are predominantly CD11ahiCD44hiCD62L−, indicative of antigen-experienced effector cells. Followingin vitrorestimulation with malaria-infected hepatocytes, CD11c+CD8+T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), perforin, and CD107a. CD11c−CD8+T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8+T cells. Coculture of CD11c+, but not CD11c−, CD8+T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8+T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c+CD8+T cell response, but CD11c expression was lost as the CD8+T cells entered the memory phase. Further analyses showed that CD11c+CD8+T cells are primarily KLRG1+CD127−terminal effectors, whereas all KLRG1−CD127+memory precursor effector cells are CD11c−CD8+T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes.

scholarly journals Phenotypic Characterization of Circulating CD4+ T Cells in ANCA-Associated Vasculitis

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Sandra Lilliebladh ◽  
Åsa Johansson ◽  
Åsa Pettersson ◽  
Sophie Ohlsson ◽  
Thomas Hellmark
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptors ◽  
Th17 Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Phenotypic Characterization ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Cytokines And Chemokines

T cell-mediated immune responses are thought to play an important role in the pathogenesis of anti-neutrophil cytoplasmic antibody- (ANCA-) associated vasculitides (AAV). CD4+ T cells can be divided into subsets depending on their expression of chemokine receptors. In this study, different CD4+ T cell populations in patients with AAV were analysed and compared to healthy blood donors as well as therapy controls. 18 patients with active AAV, 46 in remission, 21 healthy controls (HBD), and 15 therapy controls (TC) were enrolled. CD4+ T cells were divided into Th1, Th2, and Th17 cells and further subdivided into naïve, central memory, effector memory, and effector cells. Regulatory T cells were also analysed. Concentrations of cytokines and chemokines produced by the respective CD4+ T cell subset in plasma from 33 of the patients were measured by ELISA and compared to HBD. Clinical data were collected on all patients. CCL20 concentrations and percentages of Th17 cells (p=0.019) were elevated in AAV patients compared to HBD. AAV patients had lower percentages of naïve CD4+ T cells (p=0.0016) and a corresponding increase in proportion of effector memory CD4+ T cells when comparing to HBD (p=0.027). Therapy controls showed similar results as AAV patients. In this study, we found that CD4+ T cell phenotype distribution is altered in AAV patients, in line with previously published work. However, no differences were found between AAV patients and TC, stressing the importance of treatment impact on this kind of studies.

scholarly journals Unique Type I Interferon, Expansion/Survival Cytokines, and JAK/STAT Gene Signatures of Multifunctional Herpes Simplex Virus-Specific Effector Memory CD8+ TEM Cells Are Associated with Asymptomatic Herpes in Humans

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Hawa Vahed ◽  
Anshu Agrawal ◽  
Ruchi Srivastava ◽  
Swayam Prakash ◽  
Pierre-Gregoire A. Coulon ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Type I Interferon ◽  
Effector Memory ◽  
Type I ◽  
Gene Signatures ◽  
Specific Effector ◽  
Simplex Virus

ABSTRACT A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpesvirus infection and disease. However, the genomic, phenotypic, and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who, despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that memory CD8+ T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I), and JAK/STAT pathways. Frequent multifunctional HSV-specific effector memory CD62Llow CD44high CD8+ TEM cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62Lhigh CD44high CD8+ TCM cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8+ T cells from “naturally protected” ASYMP individuals will help design future T-cell-based ocular herpes immunotherapeutic vaccines. IMPORTANCE A staggering number of the world population harbors herpes simplex virus 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8+ T-cell populations associated with protection seen in ASYMP individuals. Frequent multifunctional HSV-specific effector memory CD8+ TEM cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8+ TCM cells. The memory CD8+ TEM cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines, and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8+ T cells from “naturally protected” ASYMP individuals will help in the potential design of T-cell-based ocular herpes vaccines.

scholarly journals Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1888-1898 ◽  
Author(s):  
Xiuli Wang ◽  
Carolina Berger ◽  
ChingLam W. Wong ◽  
Stephen J. Forman ◽  
Stanley R. Riddell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Central Memory ◽  
Model Systems ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
T Cell Therapy ◽  
Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

scholarly journals Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 241-250 ◽  
Author(s):  
Daniel J. Powell ◽  
Mark E. Dudley ◽  
Paul F. Robbins ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Late Stage ◽  
Adoptive Cell Transfer ◽  
Effector Memory ◽  
Cell Transfer ◽  
Effector Cells

Abstract In humans, the pathways of memory T-cell differentiation remain poorly defined. Recently, adoptive cell transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen-specific CD8+ T cells during their transition from in vitro cultured effector cells to long-term persistent memory cells following ACT to 6 responding patients. Tumor-reactive T cells used for therapy were generally late-stage effector cells with a CD27Lo CD28Lo CD45RA- CD62 ligand- (CD62L-) CC chemokine receptor 7- (CCR7-) interleukin-7 receptor αLo (IL-7RαLo) phenotype. After transfer, rapid up-regulation and continued expression of IL-7Rα in vivo suggested an important role for IL-7R in immediate and long-term T-cell survival. Although the tumor antigen-specific T-cell population contracted between 1 and 4 weeks after transfer, stable numbers of CD27+ CD28+ tumor-reactive T cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T cells in vivo. At 2 months after transfer, melanoma-reactive T cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L- CCR7- profile, which may explain in part their ability to mediate tumor destruction. (Blood. 2005;105:241-250)

scholarly journals Subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques

2021 ◽  
Vol 17 (7) ◽  
pp. e1009668
Author(s):  
Takushi Nomura ◽  
Hiroyuki Yamamoto ◽  
Masako Nishizawa ◽  
Trang Thi Thu Hau ◽  
Shigeyoshi Harada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Post Infection ◽  
Clinical Manifestations ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Viral Rna ◽  
Viral Control ◽  
Cell Responses ◽  
Cynomolgus Macaques

SARS-CoV-2 infection presents clinical manifestations ranging from asymptomatic to fatal respiratory failure. Despite the induction of functional SARS-CoV-2-specific CD8+ T-cell responses in convalescent individuals, the role of virus-specific CD8+ T-cell responses in the control of SARS-CoV-2 replication remains unknown. In the present study, we show that subacute SARS-CoV-2 replication can be controlled in the absence of CD8+ T cells in cynomolgus macaques. Eight macaques were intranasally inoculated with 105 or 106 TCID50 of SARS-CoV-2, and three of the eight macaques were treated with a monoclonal anti-CD8 antibody on days 5 and 7 post-infection. In these three macaques, CD8+ T cells were undetectable on day 7 and thereafter, while virus-specific CD8+ T-cell responses were induced in the remaining five untreated animals. Viral RNA was detected in nasopharyngeal swabs for 10–17 days post-infection in all macaques, and the kinetics of viral RNA levels in pharyngeal swabs and plasma neutralizing antibody titers were comparable between the anti-CD8 antibody treated and untreated animals. SARS-CoV-2 RNA was detected in the pharyngeal mucosa and/or retropharyngeal lymph node obtained at necropsy on day 21 in two of the untreated group but undetectable in all macaques treated with anti-CD8 antibody. CD8+ T-cell responses may contribute to viral control in SARS-CoV-2 infection, but our results indicate possible containment of subacute viral replication in the absence of CD8+ T cells, implying that CD8+ T-cell dysfunction may not solely lead to viral control failure.

scholarly journals Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection

2021 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Michael Z Zulu ◽  
Brianna Doratt ◽  
Allen Jankeel ◽  
Delia Tifrea ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pregnant Women ◽  
Immune Activation ◽  
Adverse Outcomes ◽  
Effector Memory ◽  
Type I ◽  
Type I Ifn ◽  
Asymptomatic Disease ◽  
Maternal Fetal Interface

ABSTRACTPregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.

scholarly journals Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells

2021 ◽  
Vol 118 (16) ◽  
pp. e2014553118
Author(s):  
Aenne Harberts ◽  
Constantin Schmidt ◽  
Joanna Schmid ◽  
Daniel Reimers ◽  
Friedrich Koch-Nolte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Memory Cell ◽  
Effector Memory ◽  
Effector Cells ◽  
Effector Functions

The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.

scholarly journals Vaccines Elicit Highly Cross-Reactive Cellular Immunity to the SARS-CoV-2 Omicron Variant

2022 ◽  
Author(s):  
Jinyan Liu ◽  
Abishek Chandrashekar ◽  
Daniel Sellers ◽  
Julia Barrett ◽  
Michelle Lifton ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Immunity ◽  
Severe Disease ◽  
Substantial Reduction ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd8 T Cell ◽  
Antibody Responses ◽  
Effector Memory ◽  
Cell Responses

The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 Spike immunogen, resulting in increased breakthrough infections and reduced vaccine efficacy. Cellular immune responses, particularly CD8+ T cell responses, are likely critical for protection against severe SARS-CoV-2 disease. Here we show that cellular immunity induced by current SARS-CoV-2 vaccines is highly cross-reactive against the SARS-CoV-2 Omicron variant. Individuals who received Ad26.COV2.S or BNT162b2 vaccines demonstrated durable CD8+ and CD4+ T cell responses that showed extensive cross-reactivity against both the Delta and Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron-specific CD8+ T cell responses were 82-84% of WA1/2020-specific CD8+ T cell responses. These data suggest that current vaccines may provide considerable protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantial reduction of neutralizing antibody responses.

Sign in / Sign up

Export Citation Format

Share Document