scholarly journals T cell-intrinsic and -extrinsic regulation of PD-1 function

2021 ◽  
Author(s):  
Daisuke Sugiura ◽  
Kenji Shimizu ◽  
Takumi Maruhashi ◽  
Il-mi Okazaki ◽  
Taku Okazaki
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Antigenic Peptides ◽  
Antigen Receptors ◽  
Extrinsic Factors ◽  
Intrinsic Factors ◽  
Cell Responses ◽  
Rational Development ◽  
Antigen Presenting

Abstract Cancer immunotherapies that target PD-1 (programmed cell death 1) aim to destroy tumors by activating tumor-specific T cells that are otherwise inactivated by PD-1. Although these therapies have significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment, only a limited proportion of patients benefits from the therapies currently. Therefore, there is a continued need to decipher the complex biology of PD-1 to improve therapeutic efficacies as well as to prevent immune-related adverse events. Especially, the spaciotemporal context in which PD-1 functions and the properties of T cells that are restrained by PD-1 are only vaguely understood. We have recently revealed that PD-1 function is strictly restricted at the activation phase of T cell responses by the cis interactions of PD-L1 and CD80 on antigen-presenting cells, which is critical for the induction of optimal T cell responses. We also found that the sensitivity to the effects of PD-1 in T cells is essentially determined by T cell-intrinsic factors. In T cells bearing T cell antigen-receptors (TCRs) with lower affinity to antigenic peptides, PD-1 inhibits the expression of TCR-inducible genes more efficiently; thereby PD-1 preferentially suppresses low-affinity T cells. Thus, PD-1 function is coordinately regulated by various T cell-intrinsic and -extrinsic factors that alter the responsiveness of T cells and the availability of PD-1 ligands. Precise and deeper understanding of the regulatory mechanisms of PD-1 is expected to facilitate the rational development of effective and safe immunotherapies.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
Author(s):  
Beth D. Harrison ◽  
Julie A. Adams ◽  
Mark Briggs ◽  
Michelle L. Brereton ◽  
John A. Liu Yin
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Acute Myeloid ◽  
Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

scholarly journals Second Class Minors

2003 ◽  
Vol 197 (3) ◽  
pp. 375-385 ◽  
Author(s):  
Hiroeki Sahara ◽  
Nilabh Shastri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
General Strategy ◽  
Mhc Ii ◽  
Cell Responses ◽  
Antigen Presenting

CD4 T cells regulate immune responses that cause chronic graft rejection and graft versus host disease but their target antigens remain virtually unknown. We developed a new method to identify CD4 T cell–stimulating antigens. LacZ-inducible CD4 T cells were used as a probe to detect their cognate peptide/MHC II ligand generated in dendritic cells fed with Escherichia coli expressing a library of target cell genes. The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4–induced IL4i1 gene. The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by Ab major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells. Both allelic peptides bind Ab and a single alanine to methionine substitution at p2 defines nonself. These results reveal novel features of H loci that regulate CD4 T cell responses as well as provide a general strategy for identifying elusive antigens that elicit CD4 T cell responses to tumors or self-tissues in autoimmunity.

scholarly journals Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+T Cell Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Lakshmi Krishnan ◽  
Lise Deschatelets ◽  
Felicity C. Stark ◽  
Komal Gurnani ◽  
G. Dennis Sprott
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Antigen Delivery ◽  
Antigenic Peptides ◽  
Cell Responses ◽  
Tumor Protection ◽  
Melanoma Antigens

Vesicles comprised of the ether glycerolipids of the archaeonMethanobrevibacter smithii(archaeosomes) are potent adjuvants for evoking CD8+T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189and Gp10025-33delivered in archaeosomes resulted in IFN-γproducing antigen-specific CD8+T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines.

Antigen-Specific Transfer of Functional Programmed Death Ligand 1 From Antigen Presenting Cells Onto Human CD8+ T Cells Via Trogocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 584-584
Author(s):  
Regina Gary ◽  
Simon Voelkl ◽  
Ralf Palmisano ◽  
Andreas Mackensen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Programmed Death Ligand 1 ◽  
Cell Responses ◽  
Surface Molecules ◽  
Programmed Death ◽  
Antigen Presenting

Abstract Abstract 584 Specific T-cell responses are initiated by T-cell receptor (TCR) recognition of peptide-MHC-complexes on antigen presenting cells (APCs). Upon specific interaction of T cells with APCs T cells capture membrane fragments and surface molecules of APCs in a process termed trogocytosis. Exchange of membrane molecules/antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. Here, we demonstrate that human antigen-specific CD8+ T cells do acquire the co-inhibitory molecule programmed death ligand 1 (PD-L1) from mature monocyte-derived dendritic cells (mDC) and tumor cells in an antigen-specific manner. The kinetics of PD-L1 transfer revealed a maximal PD-L1 expression on antigen-specific T cells within 3–4 hours after co-incubation with antigen-pulsed APCs, being detectable up to 72 hours. Antigen-pulsed immature DCs were less effective in transfering surface molecules such as PD-L1 onto CD8+ T cells after antigen-specific recognition. Using a transwell system we could show that the acquisition of PD-L1 requires cell-cell contact. Furthermore, PD-L1 cannot be acquired by T cells from a lysate of mDCs. The transfer process is impaired after pretreatment of T cells with concanamycin A, a specific inhibitor of vacuolar ATPases, playing an important role in membrane trafficking. Moreover, fixation of DCs with glutaraldehyde completely abrogated the acquisition of PD-L1 on T cells suggesting that an active interaction between APCs and T cells is required for trogocytosis. Of importance, CD8+ T cells which acquired PD-L1 complexes, were able to induce apoptosis of neighbouring PD-1 expressing CD8+ T cells, that could be completely blocked by an anti-PD-L1 antibody. In summary our data demonstrate for the first time that human antigen-specific CD8+ T cells take up functionally active PD-L1 from APCs in an antigen-specific fashion, leading to apoptosis of PD-1 expressing T cells. The transfer of functionally active co-inhibitory molecules from APCs onto human CD8+ T cells may serve to limit clonal expansion of antigen-specific T-cell responses but may also play a major role for T-cell exhaustion in chronic infection and tumor immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Killer artificial antigen-presenting cells: a novel strategy to delete specific T cells

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3546-3552 ◽  
Author(s):  
Christian Schütz ◽  
Martin Fleck ◽  
Andreas Mackensen ◽  
Alessia Zoso ◽  
Dagmar Halbritter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Fas Ligand ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses ◽  
Antigen Presenting

Abstract Several cell-based immunotherapy strategies have been developed to specifically modulate T cell–mediated immune responses. These methods frequently rely on the utilization of tolerogenic cell–based antigen-presenting cells (APCs). However, APCs are highly sensitive to cytotoxic T-cell responses, thus limiting their therapeutic capacity. Here, we describe a novel bead-based approach to modulate T-cell responses in an antigen-specific fashion. We have generated killer artificial APCs (κaAPCs) by coupling an apoptosis-inducing α-Fas (CD95) IgM mAb together with HLA-A2 Ig molecules onto beads. These κaAPCs deplete targeted antigen-specific T cells in a Fas/Fas ligand (FasL)–dependent fashion. T-cell depletion in cocultures is rapidly initiated (30 minutes), dependent on the amount of κaAPCs and independent of activation-induced cell death (AICD). κaAPCs represent a novel technology that can control T cell–mediated immune responses, and therefore has potential for use in treatment of autoimmune diseases and allograft rejection.

scholarly journals Single dose immunization with a COVID-19 DNA vaccine encoding a chimeric homodimeric protein targeting receptor binding domain (RBD) to antigen-presenting cells induces rapid, strong and long-lasting neutralizing IgG, Th1 dominated CD4+ T cells and strong CD8+ T cell responses in mice

2020 ◽  
Author(s):  
Gunnstein Norheim ◽  
Elisabeth Stubsrud ◽  
Lise Madelene Skullerud ◽  
Branislava Stankovic ◽  
Stalin Chellappa ◽  
...  
Keyword(s):  
T Cells ◽  
Single Dose ◽  
T Cell ◽  
Receptor Binding ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Cell Responses ◽  
Antigen Presenting

AbstractThe pandemic caused by the SARS-CoV-2 virus in 2020 has led to a global public health emergency, and non-pharmaceutical interventions required to limit the viral spread are severely affecting health and economies across the world. A vaccine providing rapid and persistent protection across populations is urgently needed to prevent disease and transmission. We here describe the development of novel COVID-19 DNA plasmid vaccines encoding homodimers consisting of a targeting unit that binds chemokine receptors on antigen-presenting cells (human MIP-1α /LD78β), a dimerization unit (derived from the hinge and CH3 exons of human IgG3), and an antigenic unit (Spike or the receptor-binding domain (RBD) from SARS-CoV-2). The candidate encoding the longest RBD variant (VB2060) demonstrated high secretion of a functional protein and induced rapid and dose-dependent RBD IgG antibody responses that persisted up to at least 3 months after a single dose of the vaccine in mice. Neutralizing antibody (nAb) titers against the live virus were detected from day 7 after one dose. All tested dose regimens reached titers that were higher or comparable to those seen in sera from human convalescent COVID-19 patients from day 28. T cell responses were detected already at day 7, and were subsequently characterized to be multifunctional CD8+ and Th1 dominated CD4+ T cells. Responses remained at sustained high levels until at least 3 months after a single vaccination, being further strongly boosted by a second vaccination at day 89. These findings, together with the simplicity and scalability of plasmid DNA manufacturing, safety data on the vaccine platform in clinical trials, low cost of goods, data indicating potential long term storage at +2° to 8°C and simple administration, suggests the VB2060 candidate is a promising second generation candidate to prevent COVID-19.

scholarly journals MyD88 in antigen-presenting cells is not required for CD4+ T-cell responses during peptide nanofiber vaccination

MedChemComm ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 138-148 ◽  
Author(s):  
Youhui Si ◽  
Yi Wen ◽  
Jianjun Chen ◽  
Rebecca R. Pompano ◽  
Huifang Han ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Self Assembled ◽  
Antigen Presenting

Self-assembled peptide nanofiber vaccines trigger redundant MyD88-dependent and MyD88-independent signaling pathways in APCs and T cells.

The Immunomodulatory Drug Lenalidomide (CC5013; Revlimid), Enhances Antigen-Presenting Cell’s Function Leading to Effective Priming of CD4+ T-Lymphocytes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2391-2391
Author(s):  
Hongwei Wang ◽  
Aung Naing ◽  
Fengdong Cheng ◽  
Pedro Horna ◽  
Ildelfonso Suarez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Immune Tolerance ◽  
T Cell Responses ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Cell Responses ◽  
Cognate Antigen ◽  
Antigen Presenting

Abstract Professional antigen-presenting cells (APCs) play an important role in the initiation of antigen-specific T-cell responses. The demonstration that these cells are also required for the induction of T-cell tolerance, placed APCs at the crossroads of immune activation versus immune tolerance. Recent studies have demonstrated that the inflammatory status of the APC at the time of antigen presentation is the central determinant of T-cell priming versus T-cell tolerance. As such, therapeutic induction of inflammatory APCs might override immune tolerance and enhance the efficacy of immunotherapeutic strategies targeting hematologic tumors. Lenalidomide (CC5013) is a thalidomide analogue with immunomodulatory properties. Phase I and Phase II clinical trials in patients with myelodysplastic syndrome (MDS) have shown high frequency of erythropoietic responses, particularly in patients with 5q31 deletion associated with emergence of polyclonal lymphoid infiltrate in responding patient bone marrows. This observation raised the question as to whether immunological mechanism(s) may mediate, at least in part, the beneficial effect of CC5013 in patients with MDS. To gain further insight into the effects of Lenalidomide on APC’s function and regulation of antigen-specific CD4+ T-cell responses, we treated peritoneal elicited macrophages (PEM) and bone marrow-derived dendritic cells (DCs) with escalating concentration of Lenalidomide in vitro. Enhanced expression of both B7.1 and B7.2 co-stimulatory molecules was observed in Lenalidomide-treated APCs relative to untreated APCs. No difference in the expression of MHC class II molecules or CD40 was detected. Assessment of cytokine production by ELISA showed that Lenalidomide-treated APCs produce higher levels of TNF-a, IL-6 and IL-10 in response to LPS stimulation as compared to untreated APCs. Next, we evaluated the ability of Lenalidomide-treated APCs to present cognate antigen to naïve and tolerant CD4+ T-cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA). We found that treatment of either PEM or DC with low doses of Lenalidomide (range: 1.5–12.5 uM) significantly enhanced their antigen-presenting capabilities leading to effective priming of naïve CD4+ T-cells confirmed by their increased production of IL-2 and IFN-gamma in response to cognate antigen. Taken together, our results shows that by inducing inflammatory APCs, Lenalidomide directs the outcome of antigen-specific T-cell responses. Furthermore, they have broadened the scope of this drug as a promising adjuvant in cancer immunotherapy.

scholarly journals Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

2004 ◽  
Vol 200 (3) ◽  
pp. 297-306 ◽  
Author(s):  
Amy Morck Thomas ◽  
Lynn M. Santarsiero ◽  
Eric R. Lutz ◽  
Todd D. Armstrong ◽  
Yi-Cheng Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses ◽  
Antigen Presenting

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.

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