scholarly journals The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects

2009 ◽  
Vol 207 (1) ◽  
pp. 207-221 ◽  
Author(s):  
Cláudia C. Oliveira ◽  
Peter A. van Veelen ◽  
Bianca Querido ◽  
Arnoud de Ru ◽  
Marjolein Sluijter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Germ Line ◽  
Wide Spectrum ◽  
Cell Subset ◽  
Target Cells ◽  
Peptide Epitopes ◽  
Leader Peptides

The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b–restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells.

Human Minor Histocompatibility Antigen-Specific CD8+ T Cells Are Found Predominantly in the CD45RA+ CD62L+ Naïve T Cell Subset.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 578-578 ◽  
Author(s):  
Marie Bleakley ◽  
Audrey Mollerup ◽  
Colette Chaney ◽  
Michele Brown ◽  
Stanley R. Riddell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Target Cells ◽  
Screening Assay ◽  
Memory T Cell ◽  
Alloreactive T Cells ◽  
Selective Depletion

Abstract Graft versus host disease (GVHD) after allogeneic stem cell transplant (SCT) is initiated by the activation of alloreactive T cells by host dendritic cells (DC) in lymphoid tissue. Studies in murine models have demonstrated that selective depletion of naïve T cells abrogates GVHD in major and minor histocompatibility antigen (miH) mismatched SCT and provides for rapid reconstitution of memory T cell responses to pathogens. This suggests the memory subset may lack a sufficient repertoire of alloreactive T cells or fail to localize to sites where GVHD is initiated. If such a strategy were effective in humans, morbidity from GVHD would be reduced, but the graft versus leukemia (GVL) effect might be compromised. To explore the potential of this approach in humans, we developed a novel limiting dilution assay using DC as stimulator cells in vitro to analyze the frequency and repertoire of human miH reactive T cells in highly purified naïve and memory T cell subsets obtained from HLA identical volunteer donor pairs. For each pair, mature DC were derived by differentiation of CD14+ monocytes in vitro from one volunteer, and pure (>97%) populations of naïve (CD62L+, CD45 RA+, CD45RO-) and memory (CD45RO+) CD8 T cells were obtained by FACS sorting of CD8 enriched PBMC from the respective HLA identical sibling. Memory and naïve T cells were cultured for 12 days in 96 well plates at a range of concentrations with DC at a 30:1 ratio and IL12 (10 ng/ml), and IL15 (10 ng/ml) was added on day 7. On day 12, the wells were screened against target cells from each volunteer in a chromium release assay (CRA) to quantitative T cells with reactivity against miH. All wells with reactivity in this screening assay were subsequently expanded using anti CD3 antibody and IL2 and retested by CRA to validate the results of the screening assay. In multiple experiments using different HLA matched pairs, T cells with specific and reproducible cytotoxic activity (>15% lysis) against target cells from the DC donor but not autologous targets were only isolated from wells plated with naïve CD8 T cells, and there was no reproducible cytotoxicity from wells plated with memory T cells. This data demonstrates that miH specific CD8 T cells are found predominantly, and possibly exclusively, in the naïve T cell subset in humans. This data is consistent with a dramatically reduced repertoire of miH alloreactive T cells in the memory T cell pool and supports the development of protocols to prevent GVHD by selective depletion of CD45RA+ CD8+ T cells from the hematopoietic cell graft. However, T cells specific for miH also contribute to the GVL effect and CD45RA depletion would be expected to compromise antileukemic activity. Using the above approach for isolating miH specific CTL from naïve CD8 T cells, we have found a diverse repertoire of alloreactivity in most cultures and identified a subset of T cell lines and clones specific for miH presented selectively on hematopoietic cells. These T cells recognize primary ALL and AML samples that express the restricting HLA allele in vitro. MiH specific T cell clones can be reliably generated by this method using DC derived from monocytes of patients with advanced leukemia. Thus, it may be feasible to utilize this approach to isolate T cells specific for hematopoietic restricted miH for adoptive therapy as an adjunct to CD45RA depletion to preserve the GVL effect and allow separation of GVL from GVHD.

Human CD8+ Treg after Allogeneic Stem-Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2243-2243
Author(s):  
Tobias A.W. Holderried ◽  
Pia Sauerborn ◽  
Hye-Jung Kim ◽  
Harvey Cantor ◽  
Dominik Wolf ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Subset ◽  
Target Cells ◽  
Cytokine Stimulation

Abstract Murine CD8+ regulatory T cells (Treg) are characterized by expression of the cell surface triad CD44, CD122 and Ly49 and require the transcription factor Helios for stable regulatory function. This regulatory CD8+ T cell subset recognizes target cells through the recognition of the Qa-1-molecule (HLA-E in man), resulting in perforin-dependent elimination of target cells. Qa-1 is a MHC class Ib molecule that presents a limited repertoire of peptides that generally serve as an indicator of cellular activation and stress. Until now, CD4+ follicular T helper cells (TFH) and CD8+ effector T cells have been identified as direct target cells of CD8+ Treg. The therapeutic success of allogeneic stem-cell transplantation (allo-SCT) as an immunotherapeutic approach to treat hematological diseases is often limited by Graft-versus-Host Disease (GvHD). Major factors for the development of GvHD are allo-reactive CD4+ TFH and CD8+ effector T cells. CD4+ regulatory T cells (Treg) have been shown to be beneficial in the prevention and/or treatment of GvHD while sparing the Graft-versus-Leukemia effect. The contribution of regulatory CD8+ T cell-mediated immune responses in GvHD has not been studied so far. However, targeting CD4+ TFH and CD8+ effector T cells, CD8+ Treg are feasible candidates as additional important players in immune regulation during GvHD development. Here we have analyzed the development of CD8+ Treg after allogeneic stem-cell transplantation in humans. Using the knowledge derived from murine studies, the killer cell immunoglobulin-like receptor (KIR), the functional homologue of the murine Ly49 receptor, was used as a surface marker on CD8+ T cells to determine the human regulatory CD8+ T cell subset. In humans, CD8+ Treg also express CD44, CD122 and the transcription factor Helios similar to murine CD8+ Treg. In vitro proliferation studies with IL-2, IL-12, IL-15 and IL-18 showed dose dependent proliferation kinetics of KIR+CD8+ Treg vs KIR-CD8+ T cells. Of note, after cytokine stimulation and cell proliferation for up to 12 days, KIR+CD8+ T cells remained phenotypically stable while KIR-CD8+ T cells did not up-regulate KIR expression. Similar results were obtained in analyses of Helios expression in CD8+ Treg during cytokine stimulation. In patients after allogeneic stem-cell transplantation, CD8+ Treg development occurs early together with reconstitution of other immune cell subsets. Subsequently, CD8+ Treg reconstitution reaches its peak around day +90 after allo-SCT. Compared with samples from healthy donors, CD8+ Treg after allo-SCT show similar surface phenotype characteristics, while Helios expression is up-regulated after allo-SCT. In summary, we have further characterized the KIR+CD8+ Treg population with distinct phenotypical and functional responses to cytokine stimulation when compared with KIR-CD8+ T cells. This KIR+CD8+ regulatory T cell subset recovers early in patients after allogeneic stem-cell transplantation with comparable characteristics to CD8+ Treg from healthy donors, with the exception of an up-regulated expression of Helios in CD8+ Treg after allo-SCT. The rapid generation of CD8+ Treg during regeneration of the immune system in these patients implicates an important role for this cell subset during immune reconstitution and may control development of GvHD. Further functional analyses of KIR+CD8+ T cells in patients after allo-SCT may be helpful in understanding the involvement of CD8+ Treg in the pathogenesis of acute and chronic GvHD. Following these results, specific activation/expansion of CD8+ Treg may then lead to additional cellular immune-modulatory options for the treatment and prevention of GvHD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3463-3471 ◽  
Author(s):  
Christoph Hess ◽  
Terry K. Means ◽  
Patrick Autissier ◽  
Tonia Woodberry ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Immune System Activation ◽  
Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

scholarly journals Human CD8+ T-cells Recognizing Peptides from Mycobacterium tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

2015 ◽  
Vol 11 (3) ◽  
pp. e1004671 ◽  
Author(s):  
Krista E. van Meijgaarden ◽  
Mariëlle C. Haks ◽  
Nadia Caccamo ◽  
Francesco Dieli ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
T Cell Subset ◽  
Human T Cell

scholarly journals Selective anergy of V beta 8+ T cells in human immunodeficiency virus-infected individuals.

1994 ◽  
Vol 179 (2) ◽  
pp. 413-424 ◽  
Author(s):  
G Dadaglio ◽  
S Garcia ◽  
L Montagnier ◽  
M L Gougeon
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Clinical Status ◽  
Interleukin 2 ◽  
Cell Subset ◽  
T Cell Subset ◽  
Immunodeficiency Virus

We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.

scholarly journals Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

2002 ◽  
Vol 195 (6) ◽  
pp. 695-704 ◽  
Author(s):  
Michel Gilliet ◽  
Yong-Jun Liu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Plasmacytoid Dendritic Cells ◽  
Target Cells ◽  
Ifn Γ

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

scholarly journals CXCR5 and ICOS expression identifies a CD8 T-cell subset with TFH features in Hodgkin lymphomas

2018 ◽  
Vol 2 (15) ◽  
pp. 1889-1900 ◽  
Author(s):  
Kieu-Suong Le ◽  
Patricia Amé-Thomas ◽  
Karin Tarte ◽  
Françoise Gondois-Rey ◽  
Samuel Granjeaud ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
T Cell Subset ◽  
Tfh Cells ◽  
Key Points ◽  
Functional Features

Key Points A subset of CD8 T cells in some Hodgkin lymphomas shares phenotypic and functional features with CD4 TFH cells.

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3872-3879 ◽  
Author(s):  
Viola Hoffacker ◽  
Anja Schultz ◽  
James J. Tiesinga ◽  
Ralf Gold ◽  
Berthold Schalke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cell Subset ◽  
Cell Repertoire ◽  
T Cell Subset ◽  
Functional Studies ◽  
Circulating T Cells

Abstract Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

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