scholarly journals HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity

2003 ◽  
Vol 198 (12) ◽  
pp. 1909-1922 ◽  
Author(s):  
Souheil-Antoine Younes ◽  
Bader Yassine-Diab ◽  
Alain R. Dumont ◽  
Mohamed-Rachid Boulassel ◽  
Zvi Grossman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Memory Cells ◽  
Cell Responses ◽  
Specific Memory ◽  
Ifn Γ ◽  
Memory Cd4 T Cells

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

scholarly journals Age-Associated Change in the Frequency of Memory CD4+ T Cells Impairs Long Term CD4+ T Cell Responses to Influenza Vaccine

2004 ◽  
Vol 173 (1) ◽  
pp. 673-681 ◽  
Author(s):  
Insoo Kang ◽  
Myung Sun Hong ◽  
Helena Nolasco ◽  
Sung Hwan Park ◽  
Jin Myung Dan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Memory Cd4 T Cells

scholarly journals Comparison of the Development of SARS-Coronavirus-2-Specific Cellular Immunity, and Central Memory CD4+ T-Cell Responses Following Infection versus Vaccination

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1439
Author(s):  
Kevin M. Dennehy ◽  
Eva Löll ◽  
Christine Dhillon ◽  
Johanna-Maria Classen ◽  
Tobias D. Warm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Central Memory ◽  
Cd4 T Cell ◽  
Memory T Cell ◽  
Cell Responses ◽  
Specific Effector ◽  
Memory Cd4 T Cells

Memory T-cell responses following infection with coronaviruses are reportedly long-lived and provide long-term protection against severe disease. Whether vaccination induces similar long-lived responses is not yet clear since, to date, there are limited data comparing memory CD4+ T-cell responses induced after SARS-CoV-2 infection versus following vaccination with BioNTech/Pfizer BNT162b2. We compared T-cell immune responses over time after infection or vaccination using ELISpot, and memory CD4+ T-cell responses three months after infection/vaccination using activation-induced marker flow cytometric assays. Levels of cytokine-producing T-cells were remarkably stable between three and twelve months after infection, and were comparable to IFNγ+ and IFNγ+IL-2+ T-cell responses but lower than IL-2+ T-cell responses at three months after vaccination. Consistent with this finding, vaccination and infection elicited comparable levels of SARS-CoV-2 specific CD4+ T-cells after three months in addition to comparable proportions of specific central memory CD4+ T-cells. By contrast, the proportions of specific effector memory CD4+ T-cells were significantly lower, whereas specific effector CD4+ T-cells were higher after infection than after vaccination. Our results suggest that T-cell responses—as measured by cytokine expression—and the frequencies of SARS-CoV-2-specific central memory CD4+T-cells—indicative of the formation of the long-lived memory T-cell compartment—are comparably induced after infection and vaccination.

Wilms Tumor Protein-1-Derived 9-Mer Peptide Induces CD4 T-Cell Responses in an HLA-DR Restricted Manner

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4351-4351
Author(s):  
Shigeo Fuji ◽  
Julia Fischer ◽  
Markus Kapp ◽  
Thomas G Bumm ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Hla Dr ◽  
Ifn Γ

Abstract Abstract 4351 Wilms‘ tumor protein-1 (WT1) is one of the most investigated tumor-associated antigens (TAA) in hematological malignancies. CD8 T-cell responses against several WT1-derived peptides have been characterized and are known to contribute to disease control after allogeneic hematopoietic stem cell transplantation (HSCT). Also the identification of human leukocyte antigen (HLA) class II-restricted CD4 T-cell epitopes from WT1 is a challenging task of T-cell-based cancer immunotherapy to improve the effectiveness of WT1 peptide vaccination. We found a highly immunogenic WT1 peptide composed of only 9 amino acids having the ability to induce IFN-γ secretion in CD4 T-cells in an HLA DR-restricted manner. This finding is of great interest as it was generally accepted that HLA class II binding peptides are composed of at least 12 amino acids being recognized by CD4 T-cells, whereas HLA class I binding peptides are composed of 8–11 amino acids being recognized by CD8 T-cells (Wang et al Mol. Immunol. 2002). However, both HLA class I and class II molecules bind to primary and secondary peptide anchor motifs covering the central 9–10 amino acids. Thus, considering this common structural basis for peptide binding there is a possibility that the WT1 9-mer peptide binds to HLA class II molecules, and induces CD4 T-cell responses. IFN-γ induction in response to several WT1 9-mer peptides was screened in 24 HLA-A*02:01 positive patients with acute myeloid leukemia or myelodysplastic syndrome after allogeneic HSCT. Responses to one WT1 9-mer peptide were exclusively detected in CD3+CD4+ T-cells of 2 patients after allogeneic HSCT, but not in CD3+CD4+ T-cells of their corresponding HSC donors. CD4+ T-cell responses to this WT1 9-mer peptide exhibited high levels of functional avidity, as IFN-γ induction was detected after stimulation with 100 ng peptide per mL. Peptide-induced IFN-γ production was confirmed with IFN-γ ELISPOT assays and the HLA restriction of the T-cell response was determined by HLA blocking antibodies. The reaction was significantly blocked by anti-pan HLA class II antibody (85 % reduction), but neither by pan-HLA class I nor by anti-HLA A2 antibody. To identify the subtype of HLA class II molecule, blocking assays with antibodies against HLA-DP, HLA-DR and HLA-DQ were performed. IFN-γ induction was completely abrogated by anti-HLA-DR antibody (99 % reduction) (fig 1, p value of unpaired student‘s t-test <0.0001 for the medium control vs anti-pan HLA class II antibody or anti-HLA-DR antibody, respectively). To test whether IFN-γ was exclusively induced in CD4 T cells, CD4 or CD8 T-cells were depleted from PBMC. Whereas CD8 T-cell depletion did not affect IFN-γ induction, CD4 T-cell depletion completely abrogated the WT1 9-mer peptide induced response (fig 2). CD4 T-cells responding to the WT1 9-mer peptide were indicated to be functional cytotoxic T-cells with an effector CD4 T-cell phenotype. Longitudinal analyses demonstrated the persistence and functionality of WT1 9-mer specific CD4 T-cells in PBMC of patients even at day 1368 after allogeneic HSCT. These data indicate for the first time that a TAA-derived 9-mer peptide can induce HLA class II-restricted CD4 T-cell responses. Vaccination with the characterized WT1 9-mer peptide can enhance the induction and maintenance of not only CD4 but also indirect CD8 T-cell responses. Considering that CD4 T-cells play an important role in tumor rejection, the possibility that other TAA-derived 9-mer peptides having the potential to induce CD4 T-cell responses should be explored in other settings of tumor immunology as well to improve vaccination strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD4 T Cell Responses in Lung Tissue and Their Role in Th2 Protective Immunity

2021 ◽  
Author(s):  
◽  
Marina Catherine Goudie Harvie
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lung Tissue ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Protective Immunity ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Memory Cd4 T Cells

<p>The acquisition of protective immunity is a critical feature of the immune system. It is the unique ability of the adaptive immune response to generate and maintain long-lived antigen specific memory cells, which is the key to preventing reinfection and achieving the goal of protective immunity. The importance of secondary lymphoid tissue (such as lymph nodes) as a site of effector CD4 T cell responses and the generation, dissemination and maintenance of memory CD4 T cells is well accepted. However, a key research area needing investigation is the basic biology of the CD4 T cell, particularly the recirculation, distribution and maintenance of CD4 T cells at sites throughout the body. To address these issues we used Nippostrongylus brasiliensis as a model of CD4 mediated protective immunity, combined with G4/IL-4 reporter mice. We show that the lung environment is critical for the priming of CD4 T cells and conferring protective immunity. In contrast to others we find no protective role for the CD4 T cell population of the skin and only a minor role for the population within the gut. In a separate study we used the drug fingolimod (FTY720) to block the cellular trafficking between lymph node and lung tissue during immune responses. Interestingly, our findings show that protection against N. brasiliensis infection is maintained when CD4 T cell recirculation between the lung and lymph node is blocked. Furthermore, we reveal that peripheral lung residing CD4 T cells are sufficient for conferring protective immunity in the N. brasiliensis model, generating support for the model of effector lymphoid tissue. When N. brasiliensis experienced CD4 T cells were localised to the lung by intranasal adoptive transfer they were able to confer protection against infection in otherwise naive animals, as early as 48 hours post infection. The most striking finding of this work is the discovery that memory CD4 T cells residing in the lung that are sufficient to confer protection against reinfection. Identifying the factors in the lung and lymph node that induce and support this CD4 T cell subset will be an important area of future research given its high relevance to the design of vaccines against parasite infections.</p>

scholarly journals Memory CD4 T Cells Direct Protective Responses to Influenza Virus in the Lungs through Helper-Independent Mechanisms

2010 ◽  
Vol 84 (18) ◽  
pp. 9217-9226 ◽  
Author(s):  
John R. Teijaro ◽  
David Verhoeven ◽  
Carly A. Page ◽  
Damian Turner ◽  
Donna L. Farber
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cd4 T Cells ◽  
Natural Infection ◽  
Influenza Virus Infection ◽  
Cd4 T Cell ◽  
Virus Challenge ◽  
Specific Memory ◽  
Memory Cd4 T Cells

ABSTRACT Memory CD4 T cells specific for influenza virus are generated from natural infection and vaccination, persist long-term, and recognize determinants in seasonal and pandemic influenza virus strains. However, the protective potential of these long-lived influenza virus-specific memory CD4 T cells is not clear, including whether CD4 T-cell helper or effector functions are important in secondary antiviral responses. Here we demonstrate that memory CD4 T cells specific for H1N1 influenza virus directed protective responses to influenza virus challenge through intrinsic effector mechanisms, resulting in enhanced viral clearance, recovery from sublethal infection, and full protection from lethal challenge. Mice with influenza virus hemagglutinin (HA)-specific memory CD4 T cells or polyclonal influenza virus-specific memory CD4 T cells exhibited protection from influenza virus challenge that occurred in the presence of CD8-depleting antibodies in B-cell-deficient mice and when CD4 T cells were transferred into lymphocyte-deficient RAG2−/− mice. Moreover, the presence of memory CD4 T cells mobilized enhanced T-cell recruitment and immune responses in the lung. Neutralization of gamma interferon (IFN-γ) production in vivo abrogated memory CD4 T-cell-mediated protection from influenza virus challenge by HA-specific memory T cells and heterosubtypic protection by polyclonal memory CD4 T cells. Our results indicate that memory CD4 T cells can direct enhanced protection from influenza virus infection through mobilization of immune effectors in the lung, independent of their helper functions. These findings have important implications for the generation of universal influenza vaccines by promoting long-lived protective CD4 T-cell responses.

scholarly journals Characterization of Respiratory Syncytial Virus M- and M2-Specific CD4 T Cells in a Murine Model

2009 ◽  
Vol 83 (10) ◽  
pp. 4934-4941 ◽  
Author(s):  
Jie Liu ◽  
Tracy J. Ruckwardt ◽  
Man Chen ◽  
Teresa R. Johnson ◽  
Barney S. Graham
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Rsv Infection ◽  
Ifn Γ ◽  
Syncytial Virus

ABSTRACT CD4 T cells have been shown to play an important role in the immunity and immunopathogenesis of respiratory syncytial virus (RSV) infection. We identified two novel CD4 T-cell epitopes in the RSV M and M2 proteins with core sequences M213-223 (FKYIKPQSQFI) and M227-37 (YFEWPPHALLV). Peptides containing the epitopes stimulated RSV-specific CD4 T cells to produce gamma interferon (IFN-γ), interleukin 2 (IL-2), and other Th1- and Th2-type cytokines in an I-Ab-restricted pattern. Construction of fluorochrome-conjugated peptide-I-Ab class II tetramers revealed RSV M- and M2-specific CD4 T-cell responses in RSV-infected mice in a hierarchical pattern. Peptide-activated CD4 T cells from lungs were more activated and differentiated, and had greater IFN-γ expression, than CD4 T cells from the spleen, which, in contrast, produced greater levels of IL-2. In addition, M209-223 peptide-activated CD4 T cells reduced IFN-γ and IL-2 production in M- and M2-specific CD8 T-cell responses to Db-M187-195 and Kd-M282-90 peptides more than M225-39 peptide-stimulated CD4 T cells. This correlated with the fact that I-Ab-M209-223 tetramer-positive cells responding to primary RSV infection had a much higher frequency of FoxP3 expression than I-Ab-M226-39 tetramer-positive CD4 T cells, suggesting that the M-specific CD4 T-cell response has greater regulatory function. Characterization of epitope-specific CD4 T cells by novel fluorochrome-conjugated peptide-I-Ab tetramers allows detailed analysis of their roles in RSV pathogenesis and immunity.

scholarly journals CD4 T–cell memory can persist in the absence of class II

2000 ◽  
Vol 355 (1395) ◽  
pp. 407-411 ◽  
Author(s):  
Susan L. Swain
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Specific Antigen ◽  
Class Ii ◽  
Cd4 T Cell ◽  
T Cell Memory ◽  
Memory Cells ◽  
Short Period ◽  
Memory Cd4 T Cells

To understand how memory CD4 T cells are generated we have re–examined the requirements for continuing antigen stimulation in the generation and persistence of this population. We find that specific antigen is only required for a short period during the activation of naive CD4 Tcells and is not required for memory generation from activated CD4 T cells or for persistence of resting memory cells generated by transfer of activated CD4 to adoptive hosts. Moreover, transfer of activated CD4 T cells to class–II–deficient hosts, indicates that T cR–class II major histocompatibility interaction is also unnecessary for either the transition from activated CD4 T cell to resting memory cells or for persistence over an eightweek period. Thus the signals regulating generation and maintenance of memory are fundamentally different from those which regulate the expansion of effector CD4 T–cell populations which include antigen itself and the CD4 T–cell autocrine cytokines induced by antigen.

scholarly journals AB0025 CITRULLINATED-PEPTIDE SPECIFIC CD4+ T CELL RESPONSES IN RHEUMATOID ARHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.2-1046
Author(s):  
J. Swift ◽  
J. Stanway ◽  
I. Nicorescu ◽  
C. Hilkens ◽  
F. Stevenaert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytokine Production ◽  
Peptide Pool ◽  
Cd4 T Cell ◽  
Research Support ◽  
Ifn Γ ◽  
Memory Cd4 T Cells ◽  
Citrullinated Peptide

Background:CD4+ T cells reacting to post-translationally modified, citrullinated self-antigens are thought to play a central role in the pathogenesis of rheumatoid arthritis (RA)1. This is evidenced by a strong HLA class II association, the success of therapeutic co-stimulation blockade and the detection of autoantigen specific T-cells using HLA class II multimers2. These cells may represent a target for antigen-specific, tolerogenic therapies and their in-depth phenotyping may provide the means by which to monitor such treatment.Objectives:To identify the citrullinated-peptide (cit-peptide) induced cytokine repertoire of antigen-specific memory CD4+ T cells in both healthy controls (HCs) and ACPA positive RA patients using intracellular cytokine staining and flow cytometry. Of note, the HLA-types of both HCs and RA patients were not known.Methods:Cryopreserved peripheral blood mononuclear cells (PBMC) from both HCs (n = 8) and RA patients (n = 13) with both early (untreated) and established disease were thawed and labelled with a proliferation tracking dye (PTD). Labelled PBMC were then either incubated alone or with a pool of cit-peptides for 9-days, followed by a 5-hour restimulation with PMA and ionomycin, where cytokine secretion was blocked for the final 4-hours using brefeldin-A. Cells were then harvested, permeabilised and stained for T cell surface markers and intracellular cytokines including IFN-γ, IL-4, IL-21 and IL-17. Stained cells were immediately acquired using a BD Fortessa X20, where antigen-specific CD4+ T cells were identified as the viable CD45RO+ (memory) CD4+ T cell population that had proliferated (PTDlow) in response to the cit-peptides. Stimulation indices (SI) were calculated as the percentage of proliferated memory CD4+ T cells in the stimulated wells divided by the percentage in the unstimulated conditions, and cit-peptide responders were defined as those with an SI > 2.0. Net cytokine production was measured by subtracting the percentage cytokine production from unstimulated CD4+ CD45RO+ PTDlow cells, from those stimulated with the cit-peptides.Results:Comparable proliferative responses were observed in both donor groups in response to stimulation with the cit-peptide pool, where 37 % of HCs and 31 % of RA patients responded with an SI > 2.0 (Fig. 1A). While little cytokine production was observed in the cit-peptide responding HC T cells, for responding RA donors, cit-peptide responsive CD4+ memory T cells were predominantly IFN-γ and IL-21 producing (Fig. 1B and 1C). In contrast, these donors did not produce significant levels of either IL-17 or IL-4 (Fig. 1D and 1E).Conclusion:Cit-peptides were able to induce proliferation in both HCs and RA memory CD4+ T cells which, amongst the RA donors only, were of a Th1/Tfh subtype. In contrast, and while based only on a small sample, cit-peptides did not induce either IL-17 or IL-4 production in either donor group, suggesting a lack of Th17/Th2 responses. Not all donors responded to the peptide pool, possibly reflecting the limited number of pooled cit-peptides or to a lack of confirmed HLA-DRB1*04:01 positive donors, as peptides were selected for their specificity on this basis. Future work will therefore include HLA-typing, as well as the inclusion of additional citrullinated-epitopes to demonstrate autoreactivity in a wider cross-section of patients. Further phenotyping of the cit-peptide specific T cells will be performed, and future plans will be to study the assay data alongside clinical outcomes to assess its value for immune monitoring.References:[1]Malmström, V et al Nat Rev Immunol. 2017; 17(1):60-75.[2]Gerstner, C et al BMC Immunol. 2020; 21(27):1-14.Disclosure of Interests:Jessica Swift: None declared, James Stanway: None declared, Ioana Nicorescu: None declared, Catharien Hilkens: None declared, Frederik Stevenaert Employee of: Janssen, Amy Anderson Grant/research support from: Pfizer, GSK and Janssen, Arthur Pratt Grant/research support from: Pfizer, GSK and Janssen, John D Isaacs Speakers bureau: Abbvie, Gilead, Roche, UC, Consultant of: Abbvie, Gilead, Roche, UC, Grant/research support from: Pfizer, GSK and JanssenFigure 1.Citrullinated-peptide specific memory CD4+ T cell proliferation (A) and net % cytokine production of IFN-γ (B), IL-21 (C), IL-17 (D) and IL-4 (E) positive cells.

scholarly journals CD4 T Cell Responses in Lung Tissue and Their Role in Th2 Protective Immunity

2021 ◽  
Author(s):  
◽  
Marina Catherine Goudie Harvie
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lung Tissue ◽  
Cd4 T Cells ◽  
Lymphoid Tissue ◽  
Protective Immunity ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Memory Cd4 T Cells

<p>The acquisition of protective immunity is a critical feature of the immune system. It is the unique ability of the adaptive immune response to generate and maintain long-lived antigen specific memory cells, which is the key to preventing reinfection and achieving the goal of protective immunity. The importance of secondary lymphoid tissue (such as lymph nodes) as a site of effector CD4 T cell responses and the generation, dissemination and maintenance of memory CD4 T cells is well accepted. However, a key research area needing investigation is the basic biology of the CD4 T cell, particularly the recirculation, distribution and maintenance of CD4 T cells at sites throughout the body. To address these issues we used Nippostrongylus brasiliensis as a model of CD4 mediated protective immunity, combined with G4/IL-4 reporter mice. We show that the lung environment is critical for the priming of CD4 T cells and conferring protective immunity. In contrast to others we find no protective role for the CD4 T cell population of the skin and only a minor role for the population within the gut. In a separate study we used the drug fingolimod (FTY720) to block the cellular trafficking between lymph node and lung tissue during immune responses. Interestingly, our findings show that protection against N. brasiliensis infection is maintained when CD4 T cell recirculation between the lung and lymph node is blocked. Furthermore, we reveal that peripheral lung residing CD4 T cells are sufficient for conferring protective immunity in the N. brasiliensis model, generating support for the model of effector lymphoid tissue. When N. brasiliensis experienced CD4 T cells were localised to the lung by intranasal adoptive transfer they were able to confer protection against infection in otherwise naive animals, as early as 48 hours post infection. The most striking finding of this work is the discovery that memory CD4 T cells residing in the lung that are sufficient to confer protection against reinfection. Identifying the factors in the lung and lymph node that induce and support this CD4 T cell subset will be an important area of future research given its high relevance to the design of vaccines against parasite infections.</p>

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