Effect of granulocyte-macrophage colony stimulating factor (GM-CSF) administered with a multipeptide vaccine on circulating CD8+ and CD4+ T-cell responses: Outcome of a multicenter randomized trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
C. L. Slingluff ◽  
G. R. Petroni ◽  
W. C. Olson ◽  
M. E. Smolkin ◽  
M. I. Ross ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
T Cell Responses ◽  
Response Rates ◽  
T Cell Response ◽  
Gm Csf ◽  
Cell Responses ◽  
Helper Peptide

3008 Background: GM-CSF administered locally with vaccines can augment T-cell responses in animal models. Human experience with GM-CSF has mostly occurred in uncontrolled or nonrandomized trials. Thus, a multicenter prospective randomized phase II trial was performed to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine administered in an emulsion with an incomplete Freund's adjuvant (IFA). A second component of the trial was designed to assess whether the vaccine administered in two sites is more immunogenic than in a single site. Methods: 121 eligible and evaluable patients with resected stage IIB-IV melanoma were administered a sequence of multipeptide vaccines, each consisting of 12 MHC Class I-restricted melanoma peptides (12MP) to stimulate CD8+ T cells, plus an HLA-DR restricted tetanus helper peptide to stimulate CD4+ T cells. Peptides were emulsified with IFA, with or without GM-CSF. T cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis, weekly x 8. Clinical outcome was evaluated for all patients. Results: Vaccination was well-tolerated, and each peptide was immunogenic. Overall CD8+ T-cell response rates to the 12MP (days 1–50), for patients vaccinated with or without GM-CSF were 43% and 75%, respectively (p < 0.001), and response magnitude was almost twice as high in patients without GM-CSF. Class I MHC tetramer analyses corroborated the functional data. There was also a greater CD4+ T-cell response to the tetanus helper peptide without GM-CSF than with it (95% and 77%, respectively, p = 0.005). There was no significant difference in immune response rates by the number of vaccine sites. For the entire patient group, 3-year overall and disease-free survival estimates [95% CI] were 76% [67, 83%] and 52% [43, 61%], respectively. There have been too few events to assess differences in clinical outcome by study arm. Conclusions: High immune response rates were achieved with this multipeptide vaccine, but CD8+ and CD4+ T-cell responses appear to be partially suppressed with addition of GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. [Table: see text]

The Response to Repeated Vaccination with PR1 and WT1 Peptides Admixed in Montanide Adjuvant Is Transient and Fails to Induce Sustained Anti-Leukemia Responses in Patients with Myeloid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4096-4096
Author(s):  
Katayoun Rezvani ◽  
Agnes S. M. Yong ◽  
Stephan Mielke ◽  
Behnam Jafarpour ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Gm Csf ◽  
Cell Responses ◽  
Ifn Γ

Abstract Abstract 4096 Poster Board III-1031 We previously demonstrated the immunogenicity of a combined vaccine approach employing two leukemia-associated antigenic peptides, PR1 and WT1 (Rezvani Blood 2008). Eight patients with myeloid malignancies received one subcutaneous 0.3 mg and 0.5 mg dose each of PR1 and WT1 vaccines in Montanide adjuvant, with 100 μg of granulocyte-macrophage colony-stimulating factor (GM-CSF). CD8+ T-cell responses against PR1 or WT1 were detected in all patients as early as 1 week post-vaccination. However, responses were only sustained for 3-4 weeks. The emergence of PR1 or WT1-specific CD8+ T-cells was associated with a significant but transient reduction in minimal residual disease (MRD) as assessed by WT1 expression, suggesting a vaccine-induced anti-leukemia response. Conversely, loss of response was associated with reappearance of WT1 transcripts. We hypothesized that maintenance of sustained or at least repetitive responses may require frequent boost injections. We therefore initiated a phase 2 study of repeated vaccination with PR1 and WT1 peptides in patients with myeloid malignancies. Five patients with acute myeloid leukemia (AML) and 2 patients with myelodysplastic syndrome (MDS) were recruited to receive 6 injections at 2 week intervals of PR1 and WT1 in Montanide adjuvant, with GM-CSF as previously described. Six of 7 patients completed 6 courses of vaccination and follow-up as per protocol, to monitor toxicity and immunological responses. Responses to PR1 or WT1 vaccine were detected in all patients after only 1 dose of vaccine. However, additional boosting did not further increase the frequency of PR1 or WT1-specific CD8+ T-cell response. In 4/6 patients the vaccine-induced T-cell response was lost after the fourth dose and in all patients after the sixth dose of vaccine. To determine the functional avidity of the vaccine-induced CD8+ T-cell response, the response of CD8+ T-cells to stimulation with 2 concentrations of PR1 and WT1 peptides (0.1 and 10 μM) was measured by IC-IFN-γ staining. Vaccination led to preferential expansion of low avidity PR1 and WT1 specific CD8+ T-cell responses. Three patients (patients 4, 6 and 7) returned 3 months following the 6th dose of PR1 and WT1 peptide injections to receive a booster vaccine. Prior to vaccination we could not detect the presence of PR1 and WT1 specific CD8+ T-cells by direct ex-vivo tetramer and IC-IFN-γ assay or with 1-week cultured IFN-γ ELISPOT assay, suggesting that vaccination with PR1 and WT1 peptides in Montanide adjuvant does not induce memory CD8+ T-cell responses. This observation is in keeping with recent work in a murine model where the injection of minimal MHC class I binding peptides derived from self-antigens mixed with IFA adjuvant resulted in a transient effector CD8+ T cell response with subsequent deletion of these T cells and failure to induce CD8+ T cell memory (Bijker J Immunol 2007). This observation can be partly explained by the slow release of vaccine peptides from the IFA depot without systemic danger signals, leading to presentation of antigen in non-inflammatory lymph nodes by non-professional antigen presenting cells (APCs). An alternative explanation for the transient vaccine-induced immune response may be the lack of CD4+ T cell help. In summary these data support the immunogenicity of PR1 and WT1 peptide vaccines. However new approaches will be needed to induce long-term memory responses against leukemia antigens. To avoid tolerance induction we plan to eliminate Montanide adjuvant and use GM-CSF alone. Supported by observations that the in vivo survival of CD8+ T-effector cells against viral antigens are improved by CD4+ helper cells, we are currently attempting to induce long-lasting CD8+ T-cell responses to antigen by inducing CD8+ and CD4+ T-cell responses against class I and II epitopes of WT1 and PR1. Disclosures: No relevant conflicts of interest to declare.

Dissecting The Potential Role Of Prevnar As An Anti-Myeloma Vaccine

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1980-1980
Author(s):  
Kimberly Noonan ◽  
Lakshmi Rudraraju ◽  
Anna Ferguson ◽  
Amy Sidorski ◽  
Andrea Casildo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Plasma Cells ◽  
T Cell Responses ◽  
Fold Increase ◽  
T Cell Response ◽  
Cell Phenotype ◽  
Cell Responses

Abstract Background Prevnar, is a multi-valent conjugate vaccine given to children and adults over 50 for the prevention of Streptococcus pneumonia, otis media and pneumococcal pneumonia. The conjugate in Prevnar is a CRM-197 protein molecule which is a nontoxic recombinant Diphtheria toxin. Prevnar serves as an excellent tool in monitoring overall immune response changes in myeloma patients’ pre and post treatment. Humoral B-cell responses can be measured by antibody responses to the pneumococcal antigens, while T cell responses to CRM-197. Clinical Study We previously conducted a study to determine the efficacy of lenalidomide to augment vaccine specific responses in patients with myeloma. Two cohorts of patients were studied. In cohort A (N=10), the first Prevnar vaccine was given two weeks prior to starting lenalidomide and the second vaccine on day 14 of cycle 2 of lenalidomide. In cohort B (N=7), both Prevnar vaccines were given on lenalidomide (day 14 of cycle 2 and 4). As we previously reported patients in cohort B had an overall better B and T cell response to Prevnar compared to cohort A. These responses were due to an overall change in B and T cell phenotype attained with lenalidomide therapy. Results Prospectively, patients in cohort B also had an unexpected overall increase in disease response and in response duration. In Cohort A only 10% of patients responded to therapy while 60% of patients in Cohort B had a clinical response. The patients with a measurable clinical response had a 5-fold increase in the percentage of tumor specific bone marrow (BM) T cells after two vaccinations with Prevnar whereas the non-responding patients had no increase in tumor specific BM T cells. Parelleling the anti-tumor response, responders showed a 15 fold increase in CRM-197 specific BM T cells after the second vaccination. Patients with no clinical response showed minimal CRM-197 T cell immunity. CRM-197 is a specific inhibitor of HB-EGF; syndecan-1 (CD138) is an HB-EGF co-receptor as well as a marker for myeloma plasma cells. We hypothesized that HB-EGF specific responses produced by vaccination with the Prevnar vaccine, and CRM-197 specifically, may have contributed to the overall increased clinical responses in our clinical trial. Responding patients had a 5-fold increase in HB-EGF specific BM T cells after vaccine 2 while clinical non-responders had no increase in HB-EGF specific BM T cells. T cells specificity for purified HB-EGF correlated with both CRM-197 and tumor specific responses. Finally the myeloma cell lines U266, H929, KMS-11 and KMS-12 co-stained for CD138 and HB-EGF with 47% of CD138+ myeloma cells co-expressing HB-EGF. Conclusions We hypothesize that the CRM-197 moiety of the Prevnar vaccine can prime T cell responses against HB-EGF on plasma cells. This immune response, in turn, weakens the tumor stromal interactions in the tumor microenvironment and potentially enhances the anti-tumor efficacy of immunomodulatory drugs such as lenalidomide. Therefore, Prevnar may possibly serve as a candidate anti-myeloma vaccine. Disclosures: No relevant conflicts of interest to declare.

EBV-positive lymphoma patients have a selective deficiency in EBV immunity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21032-21032
Author(s):  
K. N. Heller ◽  
P. G. Steinherz ◽  
C. S. Portlock ◽  
C. Münz
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

scholarly journals CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses

2003 ◽  
Vol 198 (6) ◽  
pp. 889-901 ◽  
Author(s):  
Susmit Suvas ◽  
Uday Kumaraguru ◽  
Christopher D. Pack ◽  
Sujin Lee ◽  
Barry T. Rouse
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Function ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Reactivity ◽  
Cell Responses

Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell–mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity.

scholarly journals Identification of Epitopes of Fibronectin Attachment Protein (FAP-A) of Mycobacterium avium Which Stimulate Strong T-Cell Responses in Mice

1998 ◽  
Vol 66 (3) ◽  
pp. 1261-1264 ◽  
Author(s):  
Matthew A. Holsti ◽  
Jeffrey S. Schorey ◽  
Eric J. Brown ◽  
Paul M. Allen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Mycobacterium Avium ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Protective Immune Response ◽  
Attachment Protein ◽  
Cell Responses

ABSTRACT The T-cell response to fibronectin attachment protein (FAP-A) in BALB/c and B10.BR mice was examined. Both strains developed strong T-cell responses to FAP-A, directed to single, unique epitopes. T cells from mice infected with Mycobacterium avium responded to FAP-A, suggesting a possible role in a protective immune response.

scholarly journals 126. Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection and Vaccination

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S77-S77
Author(s):  
Thomas M Snyder ◽  
Rachel M Gittelman ◽  
Mark Klinger ◽  
Damon H May ◽  
Edward J Osborne ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Natural Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Tcr Repertoire ◽  
Repertoire Sequencing

Abstract Background T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3–7 = 85.1%; Day 8–14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with &gt; 99% specificity. Conclusion TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

443 An immunotherapy trio in advanced HNSCC for coordinated B and T cell antigen response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A469-A469
Author(s):  
Bernard Fox ◽  
Tarsem Moudgil ◽  
Traci Hilton ◽  
Noriko Iwamoto ◽  
Christopher Paustian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Data Sets ◽  
Cell Responses ◽  
Anti Cancer ◽  
Bead Arrays ◽  
Hnscc Cell

BackgroundOutcomes for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are dismal and responses to anti-PD-1 appear best in tumors with PD-1+ T cells in proximity to PD-L1+ cells, arguing that improved outcome is associated with a pre-existing anti-cancer immune response. Based on this, we hypothesize that vaccines which prime and/or expand T cells to a spectrum of antigens overexpressed by HNSCC combined with T cell agonists, like anti-GITR, that provide costimulatory signals will improve the anti-PD-1 response rates. We have developed a cancer vaccine, DPV-001, that contains more than 300 proteins for genes overexpressed by HNSCC, encapsulated in a CLEC9A-targeted microvesicle and containing TLR/NOD agonists and DAMPs. Recently, we reported that combining anti-GITR + vaccine + anti-PD-1 augmented therapeutic efficacy in a preclinical model and now plan a phase 1b trial of this combination in patients with advanced HNSCC.MethodsSera from patients receiving DPV-001 as adjuvant therapy for definitively treated NSCLC, were analyzed for IgG responses to human proteins by MAP bead arrays and results compared to TCGA gene expression data sets for HNSCC. HNSCC cell lines were evaluated by RNASeq and peptides were eluted from HLA, analyzed by mass spectroscopy and correlated against MAP bead arrays and TCGA data sets. Tumor-reactive T cells from a vaccinated patient were enriched and expanded, and used in cytokine release assay (CRA) against autologous NSCLC and partially HLA matched allogeneic HNSCC cell lines.ResultsPatients receiving DPV-001 (N=13) made 147 IgG responses to at least 70 proteins for genes overexpressed by HNSCC. Preliminary evaluation of the HNSCC peptidome against the results of MAP bead array identify antigens that are target of a humoral immune response. Additionally, tumor-reactive T cells from DPV-001 vaccinated patient recognize two partially HLA-matched HNSCC targets, but not a mis-matched target.ConclusionsRecent observations from our lab and others have correlated IgG Ab responses with T cell responses to epitopes of the same protein. Based on the data summarized above, we hypothesize that we have induced T cell responses against a broad spectrum of shared cancer antigens that are common among adenocarcinomas and squamous cell cancers. Our planned clinical trial will vaccinate and boost the induced responses by costimulation with anti-GITR and then sequence in delayed anti-PD-1 to relieve checkpoint inhibition. MAP bead arrays and the peptidome library generated above will be used to assess anti-cancer B and T cell responses.Trial RegistrationNCT04470024Ethics ApprovalThe original clinical trial was approved by the Providence Portland Medical Center IRB, approval # 13-046. The proposed clinical trial has not yet been reviewed by the IRB.

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 Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

2021 ◽  
Author(s):  
Anastasia A Minervina ◽  
Mikhail V Pogorelyy ◽  
Allison M Kirk ◽  
Emma Kaitlynn Allen ◽  
Kim J Allison ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Critical Parameters ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cell Responses ◽  
Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

scholarly journals Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

2003 ◽  
Vol 77 (9) ◽  
pp. 5464-5474 ◽  
Author(s):  
Katja Nilges ◽  
Hanni Höhn ◽  
Henryk Pilch ◽  
Claudia Neukirch ◽  
Kirsten Freitag ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Response ◽  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
T Cell Responses ◽  
Cross Reactivity ◽  
Antiviral Immune Response ◽  
Human Papillomavirus Type 16 ◽  
Cell Responses

ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

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