scholarly journals CD4+ T cell immunity to Salmonella is transient in the circulation

2021 ◽  
Vol 17 (10) ◽  
pp. e1010004
Author(s):  
Newton G. Peres ◽  
Nancy Wang ◽  
Paul Whitney ◽  
Sven Engel ◽  
Meghanashree M. Shreenivas ◽  
...  
Keyword(s):  
T Cells ◽  
Bacterial Pathogen ◽  
Cd4 T Cell ◽  
Phenotypic Characteristics ◽  
Peripheral Tissues ◽  
Cell Immunity ◽  
Serovar Typhimurium ◽  
Ifn Γ ◽  
Systemic Infections ◽  
Over Time

While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.

scholarly journals Gamma Interferon-Independent Effects of Interleukin-12 on Immunity to Salmonella enterica Serovar Typhimurium

2007 ◽  
Vol 75 (12) ◽  
pp. 5753-5762 ◽  
Author(s):  
Jason D. Price ◽  
Kim R. Simpfendorfer ◽  
Radhakrishnam R. Mantena ◽  
James Holden ◽  
William R. Heath ◽  
...  
Keyword(s):  
T Cells ◽  
Salmonella Enterica ◽  
Bacterial Load ◽  
Bacterial Pathogen ◽  
Cell Receptor ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Mesenteric Lymph Nodes ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACTInterleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-γ), and various roles for IL-12 and IL-18 in control of intracellular microbial infections have been demonstrated. We used IL-12p40−/−and IL-18−/−mice to further investigate the role of IL-12 and IL-18 in control ofSalmonella entericaserovar Typhimurium. While C57BL/6 and IL-18−/−mice were able to resolve attenuatedS. entericaserovar Typhimurium infections, the IL-12p40−/−mice succumbed to a high bacterial burden after 60 days. Using ovalbumin (OVA)-specific T-cell receptor transgenic T cells (OT-II cells), we demonstrated that following oral infection with recombinantS. entericaserovar Typhimurium expressing OVA, the OT-II cells proliferated in the mesenteric lymph nodes of C57BL/6 and IL-18−/−mice but not in IL-12p40−/−mice. In addition, we demonstrated by flow cytometry that equivalent or increased numbers of T cells produced IFN-γ in IL-12p40−/−mice compared with the numbers of T cells that produced IFN-γ in C57BL/6 and IL-18−/−mice. Finally, we demonstrated that removal of macrophages fromS. entericaserovar Typhimurium-infected C57BL/6 and IL-12p40−/−mice did not affect the bacterial load, suggesting that impaired control ofS. entericaserovar Typhimurium infection in the absence of IL-12p40 is not due to reduced macrophage bactericidal activities, while IL-18−/−mice did rely on the presence of macrophages for control of the infection. Our results suggest that IL-12p40, but not IL-18, is critical to resolution of infections with attenuatedS. entericaserovar Typhimurium and that especially the effects of IL-12p40 on proliferative responses of CD4+T cells, but not the ability of these cells to produce IFN-γ, are important in the resolution of infection by this intracellular bacterial pathogen.

scholarly journals CD4+ T Cells Specific for C. difficile Toxins are a Marker of Patients with Active Relapsing Disease

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S383-S383
Author(s):  
Laura Cook ◽  
May Wong ◽  
William Rees ◽  
Torey Lau ◽  
Megan Levings ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Bacterial Pathogen ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Specific Marker ◽  
Cell Responses ◽  
Cell Immunity

Abstract Background The bacterial pathogen Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Although C. difficile infection (CDI) can be treated with antibiotics, approximately 25% of patients relapse after treatment. The pathogenicity of CDI requires the activities of its toxins, TcdA and TcdB, but T cell-mediated responses to these toxins remain uncharacterized. Methods We enrolled two cohorts of patients, one with newly acquired CDI (n = 14) and the other with relapsing CDI (n = 25); and healthy volunteers with no history of CDI (n = 12). We measured peripheral blood CD4+ T cell responses to the toxins using a whole blood flow cytometry assay that identifies antigen-specific CD4+ T cells by co-expression of CD25 and OX40 following 44h incubation with antigen (Fig 1). Results We found that in patients with recurring CDI, T cell responses to TcdB were significantly higher than in healthy controls (median 1.04% vs. 0.18%; P = 0.003, Fig 2). In contrast, TcdA T cell responses and anti-TcdA/TcdB IgG titres were not different between recurring patients and controls. TcdB, but not TcdA, T cell responses were significantly higher in recurring CDI compared with newly acquired CDI (median 1.04% vs. 0.44%; P = 0.032). In both patient cohorts TcdB-specific CD4+ T cells were functionally heterogeneous, on average: 25% expressed the gut homing marker integrin β7; there was a 1:1 ratio of Tregs to T effectors; and T effectors contained Th1, Th2 and Th17 cells at a 1.5:1:3 ratio. The proportion of Th1 and Th17 cells within TcdB-specific CD4+ T cells was also significantly reduced in recurring, compared with newly acquired, CDI (Fig 3). Analysis of sorted TcdB-specific CD25+OX40+ cells confirmed specificity for TcdB and polarization towards Th17 cells, which are important for intestinal anti-pathogen immunity. Conclusion This is the first investigation of T cell immunity to C. difficile toxins. Our data show that anti-TcdB CD4+ T cell responses are a more specific marker of disease than IgG titres. Tracking how toxin-specific CD4+ T cell responses change following treatment and/or vaccination not only has the potential to predict relapse, but also to deliver insight into how CD4+ T cell memory develops in response to this prevalent pathogen. Disclosures All authors: No reported disclosures.

scholarly journals Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Stephanie M. Dillon ◽  
Tezha A. Thompson ◽  
Allison J. Christians ◽  
Martin D. McCarter ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Older Persons ◽  
Age Groups ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

scholarly journals Prolonged Evolution of Virus-Specific Memory T Cell Immunity after Severe Avian Influenza A (H7N9) Virus Infection

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Min Zhao ◽  
Junbo Chen ◽  
Shuguang Tan ◽  
Tao Dong ◽  
Hui Jiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Avian Influenza ◽  
Influenza A ◽  
T Cell Immunity ◽  
H7n9 Virus ◽  
Specific Memory ◽  
Cell Immunity ◽  
H7n9 Infection ◽  
Over Time

ABSTRACT Since 2013, influenza A H7N9 virus has emerged as the most common avian influenza virus subtype causing human infection, and it is associated with a high fatality risk. However, the characteristics of immune memory in patients who have recovered from H7N9 infection are not well understood. We assembled a cohort of 45 H7N9 survivors followed for up to 15 months after infection. Humoral and cellular immune responses were analyzed in sequential samples obtained at 1.5 to 4 months, 6 to 8 months, and 12 to 15 months postinfection. H7N9-specific antibody concentrations declined over time, and protective antibodies persisted longer in severely ill patients admitted to the intensive care unit (ICU) and patients presenting with acute respiratory distress syndrome (ARDS) than in patients with mild disease. Frequencies of virus-specific gamma interferon (IFN-γ)-secreting T cells were lower in critically ill patients requiring ventilation than in patients without ventilation within 4 months after infection. The percentages of H7N9-specific IFN-γ-secreting T cells tended to increase over time in patients ≥60 years or in critically ill patients requiring ventilation. Elevated levels of antigen-specific CD8+ T cells expressing the lung-homing marker CD49a were observed at 6 to 8 months after H7N9 infection compared to those in samples obtained at 1.5 to 4 months. Our findings indicate the prolonged reconstruction and evolution of virus-specific T cell immunity in older or critically ill patients and have implications for T cell-directed immunization strategies. IMPORTANCE Avian influenza A H7N9 virus remains a major threat to public health. However, no previous studies have determined the characteristics and dynamics of virus-specific T cell immune memory in patients who have recovered from H7N9 infection. Our findings showed that establishment of H7N9-specific T cell memory after H7N9 infection was prolonged in older and severely affected patients. Severely ill patients mounted lower T cell responses in the first 4 months after infection, while T cell responses tended to increase over time in older and severely ill patients. Higher levels of antigen-specific CD8+ T cells expressing the lung-homing marker CD49a were detected at 6 to 8 months after infection. Our results indicated a long-term impact of H7N9 infection on virus-specific memory T cells. These findings advance our understanding of the dynamics of virus-specific memory T cell immunity after H7N9 infection, which is relevant to the development of T cell-based universal influenza vaccines.

scholarly journals Identification and Characterization of CD4+ T Cell Epitopes after Shingrix Vaccination

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Hannah Voic ◽  
Rory D. de Vries ◽  
John Sidney ◽  
Paul Rubiro ◽  
Erin Moore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Natural Infection ◽  
Clinical Manifestations ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
General Definition ◽  
Elderly Subjects ◽  
Cell Immunity

ABSTRACT Infections with varicella-zoster virus (VZV) are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox. The virus remains latent in neurons, and it can reactivate later in life, causing herpes zoster (HZ). Two different vaccines have been developed to prevent HZ; one is based on a live attenuated VZV strain (Zostavax), and the other is based on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (individuals 80 years of age and older). In this context, it is of much interest to understand if there is a role for T cell immunity in the differential clinical outcome and if there is a correlate of protection between T cell immunity and Shingrix efficacy. In this study, we characterized the Shingrix-specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets nonstructural (NS) proteins, while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule-transfected lines, we experimentally determined HLA restrictions for 94 different donor/peptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of the responding subjects. IMPORTANCE Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying the patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize the specificity, magnitude, and phenotype of VZV-specific T cells.

scholarly journals Telomerase and CD4 T Cell Immunity in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1687
Author(s):  
Magalie Dosset ◽  
Andrea Castro ◽  
Hannah Carter ◽  
Maurizio Zanetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Tumor Formation ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Current Status ◽  
Mhc Ii ◽  
Cell Immunity

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

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 CD4 T-Cell-Mediated Demyelination Is Increased in the Absence of Gamma Interferon in Mice Infected with Mouse Hepatitis Virus

2002 ◽  
Vol 76 (14) ◽  
pp. 7329-7333 ◽  
Author(s):  
Lecia Pewe ◽  
Jodie Haring ◽  
Stanley Perlman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Gamma Interferon ◽  
Cd4 T Cell ◽  
Immune Mediated ◽  
Donor Cells ◽  
Ifn Γ

ABSTRACT Mice infected with the murine coronavirus, mouse hepatitis virus, strain JHM (MHV) develop an immune-mediated demyelinating encephalomyelitis. Adoptive transfer of MHV-immune splenocytes depleted of either CD4 or CD8 T cells to infected mice deficient in recombination activation gene 1 resulted in demyelination. We showed previously that the process of CD8 T-cell-mediated demyelination was strongly dependent on the expression of gamma interferon (IFN-γ) by donor cells. In this report, we show, in contrast, that demyelination and lymphocyte infiltration were increased in recipients of IFN-γ−/− CD4 T cells when compared to levels in mice receiving C57BL/6 CD4 T cells.

CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4552-4559 ◽  
Author(s):  
Karine Serre ◽  
Adam F. Cunningham ◽  
Ruth E. Coughlan ◽  
Andreia C. Lino ◽  
Antal Rot ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cell ◽  
T Helper ◽  
T Helper 2 ◽  
Cell Responses ◽  
Cxcr3 Expression ◽  
Ifn Γ ◽  
Draining Lymph Nodes

Abstract Antibody-forming cells (AFCs) expressing the chemokine receptor CXCR3 are recruited to sites of inflammation where they help clear pathogens but may participate in autoimmune diseases. Here we identify a mechanism that induces CXCR3 expression by AFC and germinal center (GC) B cells. This happens when CD8 T cells are recruited into CD4 T cell–dependent B-cell responses. Ovalbumin-specific CD4 T cells (OTII) were transferred alone or with ovalbumin-specific CD8 T cells (OTI) and the response to subcutaneous alum-precipitated ovalbumin was followed in the draining lymph nodes. OTII cells alone induce T helper 2-associated class switching to IgG1, but few AFC or GC B cells express CXCR3. By contrast, OTI-derived IFN-γ induces most responding GC B cells and AFCs to express high levels of CXCR3, and diverse switching to IgG2a, IgG2b, with some IgG1. Up-regulation of CXCR3 by GC B cells and AFCs and their migration toward its ligand CXCL10 are shown to depend on B cells' intrinsic T-bet, a transcription factor downstream of the IFN-γR signaling. This model clarifies how precursors of long-lived AFCs and memory B cells acquire CXCR3 that causes their migration to inflammatory foci.

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