scholarly journals Immunization with short peptide particles reveals a functional CD8+ T-cell neoepitope in a murine renal carcinoma model

2021 ◽  
Vol 9 (12) ◽  
pp. e003101
Author(s):  
Xuedan He ◽  
Shiqi Zhou ◽  
Melissa Dolan ◽  
Yuhao Shi ◽  
Jianxin Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Vaccine ◽  
Vaccine Development ◽  
Immune Checkpoint Blockade ◽  
Vaccine Adjuvant ◽  
Vaccine Adjuvants ◽  
Functional Responses ◽  
Class I Mhc ◽  
Mhc I ◽  
Multiple Orders

BackgroundInduction of CD8+ T cells that recognize immunogenic, mutated protein fragments in the context of major histocompatibility class I (MHC-I) is a pressing challenge for cancer vaccine development.MethodsUsing the commonly used murine renal adenocarcinoma RENCA cancer model, MHC-I restricted neoepitopes are predicted following next-generation sequencing. Candidate neoepitopes are screened in mice using a potent cancer vaccine adjuvant system that converts short peptides into immunogenic nanoparticles. An identified functional neoepitope vaccine is then tested in various therapeutic experimental tumor settings.ResultsConversion of 20 short MHC-I restricted neoepitope candidates into immunogenic nanoparticles results in antitumor responses with multivalent vaccination. Only a single neoepitope candidate, Nesprin-2 L4492R (Nes2LR), induced functional responses but still did so when included within 20-plex or 60-plex particles. Immunization with the short Nes2LR neoepitope with the immunogenic particle-inducing vaccine adjuvant prevented tumor growth at doses multiple orders of magnitude less than with other vaccine adjuvants, which were ineffective. Nes2LR vaccination inhibited or eradicated disease in subcutaneous, experimental lung metastasis and orthotopic tumor models, synergizing with immune checkpoint blockade.ConclusionThese findings establish the feasibility of using short, MHC-I-restricted neoepitopes for straightforward immunization with multivalent or validated neoepitopes to induce cytotoxic CD8+ T cells. Furthermore, the Nes2LR neoepitope could be useful for preclinical studies involving renal cell carcinoma immunotherapy.

Platelet MHC Class I Mediates CD8+ T Cell Suppression During Sepsis

Blood ◽  
2021 ◽  
Author(s):  
Li Guo ◽  
Sikui Shen ◽  
Jesse W Rowley ◽  
Neal D. Tolley ◽  
Wenwen Jia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cd8 T Cell ◽  
Class I ◽  
Functional Responses ◽  
Class I Mhc ◽  
Mhc I

Circulating platelets interact with leukocytes to modulate host immune and thrombotic responses. In sepsis, platelet-leukocyte interactions are increased, and have been associated with adverse clinical events, including increased platelet-T cell interactions. Sepsis is associated with reduced CD8+ T cell numbers and functional responses, but whether platelets regulate CD8+ T cell responses during sepsis remains unknown. In our current study, we systemically evaluated platelet antigen internalization and presentation through major histocompatibility complex class I (MHC-I) and their effects on antigen specific CD8+ T cells in sepsis in vivo and ex vivo. We discovered that both human and murine platelets internalize and proteolyze exogenous antigens, generating peptides that are loaded onto MHC-I. The expression of platelet MHC-I, but not platelet MHC-II, is significantly increased in human and murine platelets during sepsis and in human megakaryocytes stimulated with agonists generated systemically during sepsis (e.g., IFN-g and LPS). Upregulation of platelet MHC-I during sepsis increases antigen cross-presentation and interactions with CD8+ T cells in an antigen-specific manner. Using a platelet lineage specific MHC-I deficient mouse strain (B2mf/f--Pf4Cre), we demonstrate that platelet MHC-I regulates antigen-specific CD8+ T cell proliferation in vitro, as well as the number and functional responses of CD8+ T cells in vivo during sepsis. Loss of platelet MHC-I reduced sepsis-associated mortality in mice in an antigen specific setting. These data identify a new mechanism by which platelets, through MHC-I, process and cross-present antigens, engage antigen specific CD8+ T cells, and regulate CD8+ T cell number, functional responses, and outcomes during sepsis.

scholarly journals Bacterial Protein Secretion Is Required for Priming of CD8+ T Cells Specific for the Mycobacterium tuberculosis Antigen CFP10

2008 ◽  
Vol 76 (9) ◽  
pp. 4199-4205 ◽  
Author(s):  
Joshua S. Woodworth ◽  
Sarah M. Fortune ◽  
Samuel M. Behar
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Mycobacterial Antigens

ABSTRACT Mycobacterium tuberculosis infection elicits antigen-specific CD8+ T cells that are required to control disease. It is unknown how the major histocompatibility complex class I (MHC-I) pathway samples mycobacterial antigens. CFP10 and ESAT6 are important virulence factors secreted by M. tuberculosis, and they are immunodominant targets of the human and murine T-cell response. Here, we test the hypothesis that CFP10 secretion by M. tuberculosis is required for the priming of CD8+ T cells in vivo. Our results reveal an explicit dependence upon the bacterial secretion of the CFP10 antigen for the induction of antigen-specific CD8+ T cells in vivo. By using well-defined M. tuberculosis mutants and carefully controlling for virulence, we show that ESX-1 function is required for the priming of CD8+ T cells specific for CFP10. CD4+ and CD8+ T-cell responses to mycobacterial antigens secreted independently of ESX-1 were unaffected, suggesting that ESX-1-dependent phagosomal escape is not required for CD8+ T-cell priming during infection. We propose that the overrepresentation of secreted proteins as dominant targets of the CD8+ T-cell response during M. tuberculosis infection is a consequence of their preferential sampling by the MHC-I pathway. The implications of these findings should be considered in all models of antigen presentation during M. tuberculosis infection and in vaccine development.

scholarly journals Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus

2012 ◽  
Vol 209 (12) ◽  
pp. 2263-2276 ◽  
Author(s):  
Tom M. McCaughtry ◽  
Ruth Etzensperger ◽  
Amala Alag ◽  
Xuguang Tai ◽  
Sema Kurtulus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Conditional Knockout ◽  
Cytokine Receptor ◽  
T Cell Subsets ◽  
Cytotoxic T Cell ◽  
Lineage Specification ◽  
Class I Mhc ◽  
Mhc I

The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Rα or common cytokine receptor γ chain (γc) genes were deleted in thymocytes just before positive selection. We found that γc expression was required to signal the differentiation of MHC class I (MHC-I)–specific thymocytes into CD8+ cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)–specific thymocytes into CD4+ T cells, even into regulatory Foxp3+CD4+ T cells which require γc signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8+ cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8+ T cells expressing Runx3d could arise without γc signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, γc-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I–selected thymocytes into functionally mature T cells.

scholarly journals The Role of HLA-G in Tumor Escape: Manipulating the Phenotype and Function of Immune Cells

2020 ◽  
Vol 10 ◽  
Author(s):  
Lu Liu ◽  
Lijun Wang ◽  
Lihong Zhao ◽  
Chen He ◽  
Ganlu Wang
Keyword(s):  
T Cells ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Human Leukocyte ◽  
Therapeutic Benefit ◽  
Tumor Escape ◽  
Class I Mhc ◽  
Mhc I ◽  
Suppressive Phenotype ◽  
And Function

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I (MHC I) molecule, and under physiological conditions, its expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where HLA-G is expected to contribute to establishment and maintenance of immune tolerance. However, the expression of HLA-G has been found in various types of tumors, and the level of its expression frequently correlates with high-grade histology and poor prognosis, raising the possibility that it may play a negative role in tumor immunity. ILT2 and ILT4, present on a broad of immune cells, have been identified as the main receptors engaging HLA-G, and their interactions have been found to allow the conversion of effectors like NK cells and T cells to anergic or unresponsive state, activated DCs to tolerogenic state, and to drive the differentiation of T cells toward suppressive phenotype. Therefore, tumors can employ HLA-G to modulate the phenotype and function of immune cells, allowing them to escape immune attack. In this review, we discuss the mechanism underlying HLA-G expression and function, its role played in each step of the tumor-immunity cycle, as well as the potential to target it for therapeutic benefit.

scholarly journals Activation of Stat-3 Is Involved in the Induction of Apoptosis After Ligation of Major Histocompatibility Complex Class I Molecules on Human Jurkat T Cells

Blood ◽  
1998 ◽  
Vol 91 (10) ◽  
pp. 3566-3573 ◽  
Author(s):  
Søren Skov ◽  
Mette Nielsen ◽  
Søren Bregenholt ◽  
Niels Ødum ◽  
Mogens H. Claesson
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Jurkat T Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex

Abstract Activation of Janus tyrosine kinases (Jak) and Signal transducers and activators of transcription (Stat) after ligation of major histocompatibility complex class I (MHC-I) was explored in Jurkat T cells. Cross-linking of MHC-I mediated tyrosine phosphorylation of Tyk2, but not Jak1, Jak2, and Jak3. In addition, the transcription factor Stat-3 was tyrosine phosphorylated in the cytoplasma and subsequently translocated to the cell nucleus. Data obtained by electrophoretic mobility shift assay suggested that the activated Stat-3 protein associates with the human serum-inducible element (hSIE) DNA-probe derived from the interferon-γ activated site (GAS) in the c-fos promoter, a common DNA sequence for Stat protein binding. An association between hSIE and Stat-3 after MHC-I ligation was directly demonstrated by precipitating Stat-3 from nuclear extracts with biotinylated hSIE probe and avidin-coupled agarose. To investigate the function of the activated Stat-3, Jurkat T cells were transiently transfected with a Stat-3 isoform lacking the transactivating domain. This dominant-negative acting Stat-3 isoform significantly inhibited apoptosis induced by ligation of MHC-I. In conclusion, our data suggest the involvement of the Jak/Stat signal pathway in MHC-I–induced signal transduction in T cells.

scholarly journals Viral infection overcomes ineffectiveness of anti-tumoral CD8+ T cell mediated cytotoxicity

2019 ◽  
Author(s):  
Fan Zhou ◽  
Justa Kardash ◽  
Hilal Bhat ◽  
Vikas Duhan ◽  
Sarah-Kim Friedrich ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
T Cell Response ◽  
Mhc I ◽  
T Cell Anergy ◽  
Mouse Melanoma Model ◽  
Melanoma Model

AbstractWith the integration of PD-1 and CTLA-4 targeting immune checkpoint blockade into cancer treatment regimes, the anti-tumoral cytotoxicity of tumor-specific CD8+T cells is well established. However, while the unresponsiveness of CD8+T cells against big tumors is mainly explained by T cell exhaustion, other factors contributing to CD8+T cell failure remain not well studied. Here we used a mouse melanoma model to study the interaction of growing tumor cells, innate immunity and CD8+T cell responses induced by viral replication. Mouse model of melanoma (B16F10-OVA) and infections with arenaviruses. Growing B16F10-OVA cells did not induce systemic ablation of tumor specific CD8+T cells. However, despite the presence of tumor-infiltrating CD8+T cells, the anti-tumoral immune response was very limited. T cell anergy against the tumor was accompanied with a strong down-regulation of MHC-I on advanced tumors. LCMV infection restored the MHC class I expression, enhanced T cell function and lead to tumor regression. This study shows that tumor progression does not necessary lead to systemic exhaustion of the anti-tumoral CD8+T cell response. Lack of innate signals is an additional reason for limited CD8+T cell mediated cytotoxicity against the tumor.

Dynamic changes of the immune infiltrate after neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4573-4573
Author(s):  
Axel Bex ◽  
Yasmin Abu-Ghanem ◽  
Johannes V. Van Thienen ◽  
Niels Graafland ◽  
Brunolf Lagerveld ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Neoadjuvant Treatment ◽  
Positive Interaction ◽  
Dynamic Changes ◽  
Class I Mhc ◽  
Who Grade ◽  
Mhc I ◽  
Biomarker Analysis ◽  
Pre Treatment

4573 Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a front-line standard of care for metastatic RCC. Neoadjuvant use of these combinations is associated with tumor downsizing, but dynamic effects on key immune biomarkers are uncertain. We report early dynamic changes in the tumour immune environment after neoadjuvant treatment with avelumab/axitinib. Methods: Neoavax is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in patients with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4N0-1M0). Partial primary tumour response (RECIST 1.1) occurring in ≥25% is the primary endpoint. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and major histocompatibility complex class I (MHC-I) were compared on paired samples (pre-treatment biopsy and nephrectomy) (NCT03341845). Results: Paired, sequential tissue from the first 24 patients was analysed for immune biomarker expression. Of these patients, 70% were ≥pT3a, 30% pN1, 58% had ISUP/WHO grade ≥3 with 8% sarcomatoid features. Compared to pre-treatment biopsy there was a significant increase in PD-L1 (p = 0.0002) and CD8+ expression (p = 0.0003) after therapy, whereas changes in CD8/GZMB+, MHC-I and CD8/CD39+ were not significant. Furthermore, neoadjuvant avelumab/axitinib therapy was associated with a significant decrease in Foxp3+ cells (p = 0.009). Conclusions: 12 weeks of neoadjuvant axitinib/avelumab treatment in ccRCC leads to significant dynamic changes in the tumour microenvironment for CD8+, PD-L1 and Foxp3+ expression. High baseline Foxp3+ infiltration is associated with an unfavorable outcome in the majority of solid tumours. The significant on-treatment decrease in Foxp3+ may account for the positive interaction seen between VEGF targeted therapy and immune checkpoint inhibitors in mRCC. If these cells represent regulatory T cells (Tregs), activated CD4 T cells or fragile Tregs remains to be determined. Clinical trial information: NCT03341845.

scholarly journals Structures of the MHC-I molecule BF2*1501 disclose the preferred presentation of an H5N1 virus-derived epitope

2020 ◽  
Vol 295 (16) ◽  
pp. 5292-5306 ◽  
Author(s):  
Xiaoying Li ◽  
Lijie Zhang ◽  
Yanjie Liu ◽  
Lizhen Ma ◽  
Nianzhi Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Highly Pathogenic Avian Influenza ◽  
Cell Mediated Immunity ◽  
Highly Pathogenic ◽  
Mhc I ◽  
Specific Pathogen ◽  
Pathogenic Avian Influenza Virus

Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens.

scholarly journals Activation of NKT Cells Protects Mice from Tuberculosis

2002 ◽  
Vol 70 (11) ◽  
pp. 6302-6309 ◽  
Author(s):  
Alissa Chackerian ◽  
Jen Alt ◽  
Vaji Perera ◽  
Samuel M. Behar
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tissue Injury ◽  
Adaptive Immune Response ◽  
Nkt Cells ◽  
Cell Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii

ABSTRACT The T-cell immune response to Mycobacterium tuberculosis is critical in preventing clinical disease. While it is generally accepted that both major histocompatibility complex class I (MHC-I)-restricted CD8+ and MHC-II-restricted CD4+ T cells are important for the immune response to M. tuberculosis, the role of non-MHC-restricted T cells is still not clearly delineated. We have previously reported that CD1d−/− mice do not differ from CD1d+/+ mice in their survival following infection with M. tuberculosis. We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M. tuberculosis, specific activation of NKT cells by the CD1d ligand α-galactosylceramide protects susceptible mice from tuberculosis. Treatment with α-galactosylceramide reduced the bacterial burden in the lungs, diminished tissue injury, and prolonged survival of mice following inoculation with virulent M. tuberculosis. The capacity of activated NKT cells to stimulate innate immunity and modulate the adaptive immune response to promote a potent antimicrobial immune response suggests that α-galactosylceramide administration could have a role in new strategies for the therapy of infectious diseases.

scholarly journals HIV disease progression correlates with the generation of dysfunctional naive CD8low T cells

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2189-2199 ◽  
Author(s):  
David Favre ◽  
Cheryl A. Stoddart ◽  
Brinda Emu ◽  
Rebecca Hoh ◽  
Jeffrey N. Martin ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Interferon Α ◽  
Hiv Disease ◽  
Peripheral Blood Mononuclear ◽  
Class I Mhc ◽  
Mhc I

Abstract HIV infection can result in depletion of total CD4+ T cells and naive CD8+ T cells, and in the generation of dysfunctional effector CD8+ T cells. In this study, we show that naive CD8+ T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8low T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8low T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3highCD8+CD4− single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8low T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.

Sign in / Sign up

Export Citation Format

Share Document