scholarly journals 91. Differential Impact of Cytomegalovirus (CMV) Donor (D) Serostatus on Rates and Kinetics of CMV Viremia among CMV Seropositive Recipients (R+) of Ex vivo T-cell Depleted (TCD) and Unmodified (CONV) Hematopoietic Cell Transplants (HCT)

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S7-S7
Author(s):  
Anat Stern ◽  
Yiqi Su ◽  
Jiaqi Fang ◽  
Miguel Perales ◽  
Molly Maloy ◽  
...  
Keyword(s):  
T Cell ◽  
Ex Vivo ◽  
Hematologic Malignancies ◽  
T Cell Immunity ◽  
Similar Frequency ◽  
Viral Loads ◽  
Cell Immunity ◽  
Cell Transplants ◽  
The Impact ◽  
Kinetics Of

Abstract Background In unmodified (CONV) HCT, CMV donor seropositivity (D+) conveys partial protection against CMV disease mediated by the transfer of donor CMV T-cell immunity through the allograft. Ex vivo T-cell depletion by CD34 selection affords a stringent depletion of donor T cells, thus transfer of donor T-cell immunity to CMV would be negligible. We evaluate the impact of CMV D serostatus on rates and kinetics of CMV viremia by Day (D)100 post-HCT in a contemporary cohort of CONV and TCD recipients from a single center. Methods A retrospective cohort study of R+ adult recipients of first peripheral blood or marrow HCT for hematologic malignancies (excluding multiple myeloma) from June 2010 to December 2017 at MSKCC. Routine CMV monitoring by a quantitative PCR assay occurred weekly from D14 through D100. Patients were treated preemptively. CMV viral burden was assessed as the time-averaged area under the viremia curve over 100 days from HCT (AAUC) calculated as the sum of the area of trapezoids of AUC viral loads divided by the number of weeks of follow-up viremia. The median AAUC for all patients with CMV reactivation (AAUC50) was used to classify patients as CMV controllers (AAUC ≤ AAUC50) or noncontrollers (AAUC >AAUC50). Results Of 509 R+, 290 (57%) patients received CONV and 219 (43%) TCD HCT; from 300 (59%) D+ and 209 (41%) D− donors. In CONV, CMV viremia occurred with similar frequency in D+ (65%) and D− (62%), P = 0.6. In contrast, in TCD, CMV viremia occurred more frequently in D+ compared with D− (83% vs. 71%, P = 0.03). Among CONV, D+ was associated with lower CMV burden (median AAUC) compared with D− (0.791 vs. 1.13, respectively, P = 0.0004). In contrast, in TCD, AAUC was similar between D− and D+ (1.19 vs. 1.35; P = 0.86). Among CONV with CMV viremia, D− were more likely to be noncontrollers compared with D+ (56% vs. 31%, respectively, P = 0.001). In contrast, among TCD with CMV viremia the proportion of noncontrollers was similar between D− and D+ (61% vs. 60%, respectively; P = 1). Conclusion Donor CMV serostatus has a differential effect on rates and kinetics of CMV viremia in R+ TCD and CONV HCT recipients. D+ is associated with less CMV viremia and less CMV burden in CONV but not in TCD. Our findings, if confirmed, have implications for donor selection algorithms. Disclosures All Authors: No reported Disclosures.

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 The immune battlefield: The impact of inflammatory cytokines on CD8+ T-cell immunity

2017 ◽  
Vol 13 (10) ◽  
pp. e1006618 ◽  
Author(s):  
Stephanie A. Condotta ◽  
Martin J. Richer
Keyword(s):  
T Cell ◽  
Inflammatory Cytokines ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
The Impact

HLA-Class I Alleles Impact Susceptibility To EBV+ Classical Hodgkin Lymphoma By Altering EBV Latent Antigen-Specific CD8+ T-Cell Immune Hierarchies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 630-630
Author(s):  
Maher K Gandhi ◽  
Rebekah M Brennan ◽  
Leesa Wockner ◽  
Pratip K Chattopadhyay ◽  
Mario Roederer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Class I ◽  
Cell Responses ◽  
Cell Immunity

Abstract In Epstein-Barr virus (EBV) classical Hodgkin lymphoma (EBV+ cHL), Hodgkin-Reed Sternberg cell antigen presentation is intact, with viral expression restricted to sub-dominant latent-antigens including LMP1/2A. Large epidemiological studies have reported differential HLA-class I (HLA-I) susceptibility to EBV+ cHL. The functional basis for these observations is unknown. HLA-I molecules present viral peptides for recognition by CD8+ T-cells, and it may be that the relative risk of developing EBV+ cHL is due to HLA-I alleles influencing the magnitude of CD8+ T-cell immunity against relevant EBV-specific antigens. However this remains speculative, with immunological evidence lacking. Several non-HLA-I linked genetic susceptibility loci have been identified, and HLA-I associations may simply represent markers for genes of diverse functions that are in linkage disequilibrium to the HLA-I region. We undertook an Australasian Leukaemia and Lymphoma Group study to address this fundamental question, utilizing 4 distinct but complimentary experimental approaches. 1. 9 EBV+ cHL and 11 EBV-ve cHL pre-therapy PBMC samples were tested for ex-vivo IFNγ, TNFα and CD107a CD8+ T-cell immunity, using overlapping LMP1 and LMP2A peptide pools. The non-HRS expressed EBV-lytic protein BZLF1 was a control. Highly stringent FACS gating was used to maximize specificity. Results were interrogated using Profile and SPICE analysis. Interestingly IFNγ, TNFα and CD107 CD8+ T-cell responses in HLA-A*02 EBV+ cHL (but not EBV-ve cHL) patients were greater than non-HLA-A*02 (LMP1 p=0.002; LMP2A p=0.03; combined LMP1/LMP2A p=0.005), whereas BZLF1 was equivalent, indicating that HLA-I provides differential CD8+ T-cell immunity against relevant EBV-latent antigens in EBV+ cHL but not EBV-ve cHL. 2. However, up to 4 different HLA-A/B molecules can potentially present relevant EBV-derived epitopes in each individual, adding a confounding layer of complexity to single allele-based effects. To overcome this and enhance sensitivity, we used the mutant HLA-I 721.221 cell-line (pulsed with LMP2A), transfected with either HLA-A*01, HLA-A*02, HLA-A*03 or HLA-B*08 alleles, as antigen presenting cells to in-vitro expand LMP2A-specific CD8+ T-cells from HLA-A*02 heterozygotes. This found ∼90% of the HLA-I LMP2A response was restricted through HLA-A*02. 3. In contrast to EBV+ cHL, in EBV-post-transplant lymphoproliferative disorders (EBV+ PTLD) the immunogenic EBNA3A/3B/3C latent-antigens are expressed. We compared HLA-I associations in 110 cHL (35% EBV+ cHL) to 153 PTLD (63% EBV+ PTLD) patients. Using Bonferoni corrected statistics, we confirmed that HLA-A*02 and HLA-A*01 homozygotes had lower and higher susceptibility to EBV+ cHL respectively, and that HLA-B*37 was positively associated. Notably, no HLA-I associations with EBV+ PTLD were found. 4. To investigate the impact of HLA-I on the hierarchy of CD8+ T-cell immunity to sub-dominant (LMP1/2A) and immune-dominant (EBNA3A/3B/3C) EBV-latent proteins, we analysed the diversity of HLA-class I restricted T-cells in 30 healthy EBV+ participants. To supplement 30 ‘defined' (i.e. validated) HLA-I EBV-latent antigen epitopes and expand HLA-I coverage, we identified 31 ‘SYFPEITHI' bioinformatically ‘predicted' peptide epitopes for HLA-A*01, HLA-A*03 or HLA-B*37 restricted EBV-latent antigens. All SYFPEITHI scores were ≥21, and thermal stability circular dichroism analysis (HLA-A*01) or MHC stabilization assays on T2 cells (HLA-A*03) confirmed peptide binding to HLA-I. Ex-vivo CD107 CD8+ T-cell assays for the 61 peptides, found that sub-dominant LMP1/2A-specific peptide responses were largely confined to HLA-A*02 (Fig 1A), whilst immuno-dominant CD8+ T-cell responses were stimulated by peptides presented by numerous HLA-I alleles (Fig 1B). These data combined illustrate that differential HLA-I-associated susceptibility to EBV+ cHL reflects altered EBV latent antigen-specific CD8+ T-cell immune hierarchies. For lymphomas expressing a restricted set of poorly immunogenic proteins, even modest CD8+ T-cell responses against relevant tumor-associated proteins confer protection, with broad implications for EBV-vaccine design. Studies are required to determine if similar mechanisms are applicable to non-lymphoid EBV+ malignancies with restricted latency such as undifferentiated nasopharngeal carcinoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity

2014 ◽  
Vol 10 (5) ◽  
pp. e1004085 ◽  
Author(s):  
Stephanie Ascough ◽  
Rebecca J. Ingram ◽  
Karen K. Chu ◽  
Catherine J. Reynolds ◽  
Julie A. Musson ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
Lethal Factor ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Hla Polymorphism ◽  
Cell Immunity ◽  
Anthrax Lethal Factor ◽  
The Impact ◽  
Immune Target

scholarly journals Identification and characterization of CD4+ T cell epitopes after Shingrix vaccination

2020 ◽  
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

AbstractInfections with varicella zoster virus (VZV), a member of the Herpesviridae family, are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox, and due to the virus’s capacity to remain latent in neurons, it can reactivate later in life causing herpes zoster (HZ), also known as shingles. Two different vaccines have been developed to prevent HZ, one based on a live attenuated VZV strain (Zostavax) and the other on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (80 years of age and beyond). In this context, it is of much interest to understand if there is a role for T cell immunity in differential clinical outcome, and if there is a correlate of protection between T cell immunity and Shingrix efficacy. In this study, we characterized 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 non-structural proteins (NS), 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 responding subjects.ImportanceUnderstanding 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 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 specificity, magnitude and phenotype of VZV specific T cells.

scholarly journals Local SARS-CoV-2 peptide-specific Immune Responses in Convalescent and Uninfected Human Lung Tissue Models

2021 ◽  
Author(s):  
Kayla F. Goliwas ◽  
Christopher S. Simmons ◽  
Saad A. Khan ◽  
Anthony M. Wood ◽  
Yong Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Tissue ◽  
Human Lung ◽  
Ex Vivo ◽  
T Cell Immunity ◽  
T Cell Subsets ◽  
Human Lung Tissue ◽  
Memory T Cell ◽  
Cell Immunity ◽  
Tissue Models

Multi-specific and long-lasting T cell immunity have been recognized as indicators for long term protection against pathogens including the novel coronavirus SARS-CoV-2, the causative agent of the COVID-19 pandemic. Functional significance of peripheral memory T cell subsets in COVID-19 convalescents (CONV) are beginning to be appreciated; but little is known about lung resident memory T cell (lung TRM) responses and their role in limiting the severity of SARS-CoV-2 infection. Here, we utilize a perfusion three dimensional (3D) human lung tissue model and identify pre-existing local T cell immunity against SARS-CoV-2 spike protein and structural antigens in the lung tissues. We report ex vivo maintenance of functional multi-specific IFN-γ secreting lung TRM in CONV and their induction in lung tissues of vaccinated CONV. Importantly, we identify SARS-CoV-2 spike peptide-responding B cells in lung tissues of CONV in ex vivo 3D-tissue models. Our study highlights a balanced and local anti-viral immune response in the lung and persistent induction of TRM cells as an essential component for future protection against SARS-CoV-2 infection. Further, our data suggest that inclusion of multiple viral antigens in vaccine approaches may broaden the functional profile of memory T cells to combat the severity of coronavirus infection.

scholarly journals Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens

2019 ◽  
Vol 116 (47) ◽  
pp. 23662-23670 ◽  
Author(s):  
Gerald P. Linette ◽  
Michelle Becker-Hapak ◽  
Zachary L. Skidmore ◽  
Miren Lorea Baroja ◽  
Chong Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Cell Receptor ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Single Nucleotide Variants ◽  
Cell Immunity ◽  
Multiple Metastases ◽  
The Impact

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαβ heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.

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