scholarly journals Neonates Mount Robust and Protective Adult-Like CD8+-T-Cell Responses to DNA Vaccines

2002 ◽  
Vol 76 (23) ◽  
pp. 11911-11919 ◽  
Author(s):  
Jie Zhang ◽  
Nicole Silvestri ◽  
J. Lindsay Whitton ◽  
Daniel E. Hassett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Viral Infections ◽  
Dna Vaccines ◽  
Neonatal Period ◽  
Cytotoxic T Cells ◽  
Lymphocytic Choriomeningitis ◽  
Cell Responses ◽  
Rapid Induction

ABSTRACT Neonates are thought to mount less vigorous adaptive immune responses than adults to antigens and infectious agents. This concept has led to a delay in the administration of many currently available vaccines until late infancy or early childhood. It has recently been shown that vaccines composed of plasmid DNA can induce both humoral and cell-mediated antimicrobial immunity when administered within hours of birth. In most of these studies, immune responses were measured weeks or months after the initial vaccination, and it is therefore questionable whether the observed responses were actually the result of priming of splenocytes within the neonatal period. Here we show that DNA vaccination at birth results in the rapid induction of antigen-specific CD8+ T cells within neonatal life. Analyses of T-cell effector functions critical for the resolution of many viral infections revealed that neonatal and adult CD8+ T cells produce similar arrays of cytokines. Furthermore, the avidities of neonatal and adult CD8+ T cells for peptide and the rapidity with which they upregulate cytokine production after recall encounters with antigen are similar. Protective immunity against the arenavirus lymphocytic choriomeningitis virus, which is mediated by CD8+ cytotoxic T cells, is also rapidly acquired within the neonatal period. Collectively these data imply that, at least in the case of CD8+ T cells, neonates are not as immunodeficient as previously supposed and that DNA vaccines may be an effective and safe means of providing critical cell-mediated antiviral immunity extremely early in life.

T-cell responses against chronic lymphocytic leukemia cells: implications for immunotherapy

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 167-173 ◽  
Author(s):  
Angela M. Krackhardt ◽  
Sabine Harig ◽  
Mathias Witzens ◽  
Ryan Broderick ◽  
Patrick Barrett ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Lymphocytic Leukemia ◽  
Cell Responses ◽  
Healthy Donors ◽  
T Cell Lines ◽  
Antigen Presenting

Abstract Chronic lymphocytic leukemia (CLL) cells are ineffective antigen-presenting cells (APCs) although CD40-activated CLL cells can stimulate proliferation of autologous and allogeneic T cells. We examined the antigen-presenting capacity of CD40-activated CLL cells as well as dendritic cells pulsed with apoptotic bodies of CLL cells to generate autologous and allogeneic immune responses against CLL cells. Both APC types were capable of generating T-cell lines that proliferate specifically in response to unstimulated CLL cells. Whereas cytotoxic responses against stimulated and unstimulated CLL cells could be repeatedly generated by allogeneic healthy donors, autologous cytotoxic immune responses against CD40-activated and native CLL cells were rarely detected. However, T cells isolated from patients with CLL could recognize and lyse allogeneic stimulated and unstimulated CLL cells, demonstrating that cytotoxic T cells from these tumor-bearing patients are functionally intact.

scholarly journals Specific Immune Responses for Leukemia-Associated Antigens Against Myeloid Leukemic Cells Are Increased By Immune Checkpoint Inhibition

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4054-4054 ◽  
Author(s):  
Jochen Greiner ◽  
Marlies Götz ◽  
Vanessa Schneider ◽  
Hubert Schrezenmeier ◽  
Markus Wiesneth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Cytotoxic T Cells ◽  
T Cell Responses ◽  
Leukemic Cells ◽  
Cell Responses ◽  
Cell Assays ◽  
T Cell Assays

Abstract Immunotherapy in cancer treatment has gained importance in the last few years. The efficacy of immunotherapeutic approaches such as immune-checkpoint inhibitors, chimeric antigen receptor T cells (CARs) or bi-specific T cell activating antibodies becomes more and more obvious. However, mechanisms of these immune responses and responsible antigen structures have to be further elucidated. Leukemia-associated antigens (LAA) represent immunogenic antigens that are candidates for specific immunotherapy since they are target structures relevant for elimination of malignant cells by cytotoxic T cells (CTL). In this work, we investigated the influence of PD-1 antibody Nivolumab and CTLA-4 antibody Ipilimumab on the antigen-specific immune responses by specific T cells against leukemic myeloid blasts in functional T cell assays using ELISpot Assays, tetramer-analysis and colony-forming immunoassays. We investigated T cell responses stimulated against known LAAs like RHAMM, PRAME, WT-1, SSXIP2, Proteinase 3, Survivin, Aurorakinase A and NPM1 against several AML cell lines and samples of AML patients. Expression of different LAAs were measured and correlated to functional T cell assays. Colony forming unit immunoassays displayed a significant inhibition of CFU (colony forming units) in AML patient samples when adding T cells stimulated against various LAA. In all patient samples, effectors activated against at least one LAA were successful to decrease the colony number significantly. The LAAs PRAME, RHAMM and WT1 showed highest frequency and intensity of immunogenic reactions: PRAME stimulated CTL induced an immune response in 83% of tested samples in CFU, stimulated with WT1 in 75% and with RHAMM in 58% of colonies from AML samples. Specific immune responses of cytotoxic T cells were additionally detected by ELISpot assays and correlated to results detected in CFU. Immune effects increased adding nivolumab to the CTL for several days before starting CFU immunoassays whereas no effect was measured when CTL were incubated with Ipilimumab. The combination of Nivolumab and Ipilimumab showed no additional effect of immune responses compared to Nivolumab alone. Taken together, the immune checkpoint inhibitor Nivolumab increases specific T cell responses of LAA-stimulated cytotoxic T cells and the cytotoxic effect of T cells against blasts of AML patients. No additional effect was detected with Ipilimumab. These data suggest that PD-1 antibodies could be an immunotherapeutic approach in AML and combination with LAA-directed vaccination strategies might open interesting application possibilities. Disclosures Greiner: BMS: Research Funding.

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Y. Lévy ◽  
C. Lacabaratz ◽  
E. Lhomme ◽  
A. Wiedemann ◽  
C. Bauduin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase Ii ◽  
Antiretroviral Treatment ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Vaccine Strategy ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.) IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

Long term results from a phase 1 trial of GEN-009, a personalized neoantigen vaccine, combined with PD-1 inhibition in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2613-2613
Author(s):  
Maura L. Gillison ◽  
Mark M. Awad ◽  
Przemyslaw Twardowski ◽  
Ammar Sukari ◽  
Melissa Lynne Johnson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Salvage Therapy ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Long Term Results ◽  
Advanced Solid Tumors ◽  
Cell Responses

2613 Background: GEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS, an ex vivo bioassay screening autologous T cells for immune responses against both neoantigens as well as Inhibigens. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice and are avoided in GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Nearly all (99%) of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively. Seven of 8 patients continue without progression with a median follow up of 18 months. Methods: GEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with a PD-1 CPI. Patients who progressed prior to vaccination received alternative salvage therapy followed by GEN-009 in combination. Peripheral T cell responses were measured by fluorospot assays in ex vivo and in vitro stimulation. Results: 15 pts received GEN-009 in combination with a PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (5-18). GEN-009-related adverse events were limited to vaccine injection site reactions and mild myalgias or fatigue. Longitudinal evaluation of ex vivo T cell responses revealed that sequential vaccination with GEN-009 had an overall additive effect on the robustness of IFNγ secretion and responses were persistent for at least 6 months in some patients. Epitope spread was detected in CPI sensitive patients, but not in CPI refractory patients receiving salvage therapy. Three patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further reduction after GEN-009 vaccination that could represent vaccine effect. Eight of 9 CPI responsive patients are progression-free from 3 to 10 months after first vaccine dose. Four of 7 CPI refractory patients have experienced unexpected prolonged stable disease after vaccination of up to 8 months after vaccination. 2 of 2 patients with available samples lost all evidence of circulating tumor DNA including non-targeted neoantigens. Conclusions: Vaccination with GEN-009 in combination with anti-PD-1 CPI in patients with advanced solid tumors shows little additive toxicity. Preliminary data demonstrate induction of broad neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study. Clinical trial information: NCT03633110.

scholarly journals T-Cell Large Granular Lymphocytic Leukemia with Extremely Rare Immunophenotype (CD4/CD8 Double-Positive) Followed by Multiple Myeloma Diagnosis

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Dina Soliman ◽  
Sherin Sallam ◽  
Susanna Akiki ◽  
Deena Mudawi ◽  
Feryal Ibrahim
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Viral Infections ◽  
Cytotoxic T Cells ◽  
Flow Cytometric Analysis ◽  
Lymphocytic Leukemia ◽  
Double Positive ◽  
Large Granular Lymphocytic Leukemia ◽  
First Case

T-cell large granular lymphocytic leukemia is characterized by clonal expansion of a CD3+/CD57+ subpopulation, which are typically CD8+ positive cytotoxic T- cells, and can only be diagnosed if there is a persistent, greater than 6 months, elevation of LGL in the blood (usually 2–20 × 109/L), in the absence of an identifiable cause. T-LGLL has been associated with reactive conditions such as autoimmune diseases and viral infections and has also been reported in association with hematologic and non-hematologic malignancies. We report a case of asymptomatic CD4/CD8 double-positive T-LGLL. Flow cytometry on peripheral blood revealed a subpopulation of CD4/CD8 double-positive T cells expressing CD57 and cTIA. Clonality was established by flow cytometric analysis of T-cell receptor V(â) region repertoire which showed that >70% of the cells failed to express any of the tested V(â) regions. Clonality was further confirmed by PCR with the detection of clonal TCR beta and TCR gamma gene rearrangements. Six months later, she presented with persistent lower back pain and diagnosed with IgG kappa multiple myeloma. CD4/CD8 double-positive T-large granular leukemia is the first case reported in the literature. This rare phenotype is either underreported or a truly rare clinical entity. More studies are warranted to characterize the pathogenesis and clinical characteristics of this group of patients and to further assess the relationship between multiple myeloma and T-LGLL as a cause-and-effect relationship or simply related to the time at which diagnosis has been made.

scholarly journals TCR Transgenic Mice: A Valuable Tool for Studying Viral Immunopathogenesis Mechanisms

2020 ◽  
Vol 21 (24) ◽  
pp. 9690
Author(s):  
Yong-Bin Cho ◽  
In-Gu Lee ◽  
Yong-Hyun Joo ◽  
So-Hee Hong ◽  
Young-Jin Seo
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Receptor ◽  
Global Economy ◽  
Viral Infections ◽  
Cell Receptor ◽  
Cell Responses ◽  
Significant Burden ◽  
Underlying Mechanisms ◽  
Remarkable Progress

Viral infectious diseases are a significant burden on public health and the global economy, and new viral threats emerge continuously. Since CD4+ and CD8+ T cell responses are essential to eliminating viruses, it is important to understand the underlying mechanisms of anti-viral T cell-mediated immunopathogenesis during viral infections. Remarkable progress in transgenic (Tg) techniques has enabled scientists to more readily understand the mechanisms of viral pathogenesis. T cell receptor (TCR) Tg mice are extremely useful in studying T cell-mediated immune responses because the majority of T cells in these mice express specific TCRs for partner antigens. In this review, we discuss the important studies utilizing TCR Tg mice to unveil underlying mechanisms of T cell-mediated immunopathogenesis during viral infections.

scholarly journals Baseline Levels of Influenza-Specific B Cells and T Cell Responses Modulate Human Immune Responses to Swine Variant Influenza A/H3N2 Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 126
Author(s):  
Lilin Lai ◽  
Nadine Rouphael ◽  
Yongxian Xu ◽  
Amy C. Sherman ◽  
Srilatha Edupuganti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza A ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Post Vaccination ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

The cellular immune responses elicited by an investigational vaccine against an emergent variant of influenza (H3N2v) are not fully understood. Twenty-five subjects, enrolled in an investigational influenza A/H3N2v vaccine study, who received two doses of vaccine 21 days apart, were included in a sub-study of cellular immune responses. H3N2v-specific plasmablasts were determined by ELISpot 8 days after each vaccine dose and H3N2v specific CD4+ T cells were quantified by intracellular cytokine and CD154 (CD40 ligand) staining before vaccination, 8 and 21 days after each vaccine dose. Results: 95% (19/20) and 96% (24/25) subjects had pre-existing H3N2v specific memory B, and T cell responses, respectively. Plasmablast responses at Day 8 after the first vaccine administration were detected against contemporary H3N2 strains and correlated with hemagglutination inhibition HAI (IgG: p = 0.018; IgA: p < 0.001) and Neut (IgG: p = 0.038; IgA: p = 0.021) titers and with memory B cell frequency at baseline (IgA: r = 0.76, p < 0.001; IgG: r = 0.74, p = 0.0001). The CD4+ T cells at Days 8 and 21 expanded after prime vaccination and this expansion correlated strongly with early post-vaccination HAI and Neut titers (p ≤ 0.002). In an adult population, the rapid serological response observed after initial H3N2v vaccination correlates with post-vaccination plasmablasts and CD4+ T cell responses.

scholarly journals Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4+ and CD8+ T-Cell Responses

2008 ◽  
Vol 82 (23) ◽  
pp. 11734-11741 ◽  
Author(s):  
Courtney Dow ◽  
Carla Oseroff ◽  
Bjoern Peters ◽  
Courtney Nance-Sotelo ◽  
John Sidney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Epitopes ◽  
Binding Assays ◽  
Cell Responses ◽  
Lymphocytic Choriomeningitis Virus Infection

ABSTRACT Activation of CD4+ T cells helps establish and sustain other immune responses. We have previously shown that responses against a broad set of nine CD4+ T-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (LCMV) Armstrong infection in the context of H-2d. This is quite disparate to the H-2b setting, where only two epitopes have been identified. We were interested in determining whether a broad set of responses was unique to H-2d or whether additional CD4+ T-cell epitopes could be identified in the setting of the H-2b background. To pursue this question, we infected C57BL/6 mice with LCMV Armstrong and determined the repertoire of CD4+ T-cell responses using overlapping 15-mer peptides corresponding to the LCMV Armstrong sequence. We confirmed positive responses by intracellular cytokine staining and major histocompatibility complex (MHC)-peptide binding assays. A broad repertoire of responses was identified, consisting of six epitopes. These epitopes originate from the nucleoprotein (NP) and glycoprotein (GP). Out of the six newly identified CD4+ epitopes, four of them also stimulate CD8+ T cells in a statistically significant manner. Furthermore, we assessed these CD4+ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4+ and CD8+ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses.

Sign in / Sign up

Export Citation Format

Share Document