scholarly journals Dimorphism of HLA-E and its Disease Association

2019 ◽  
Vol 20 (21) ◽  
pp. 5496 ◽  
Author(s):  
Leonid Kanevskiy ◽  
Sofya Erokhina ◽  
Polina Kobyzeva ◽  
Maria Streltsova ◽  
Alexander Sapozhnikov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Tertiary Structure ◽  
Hla Class I ◽  
Surface Expression ◽  
Class I ◽  
Human Populations ◽  
Cytotoxic Lymphocytes ◽  
Main Function ◽  
Mhc I ◽  
High Level

HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.

scholarly journals Variations in MHC class I antigen presentation and immunopeptidome selection pathways

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1177
Author(s):  
Anita J. Zaitouna ◽  
Amanpreet Kaur ◽  
Malini Raghavan
Keyword(s):  
Cell Surface ◽  
Antigen Presentation ◽  
Surface Expression ◽  
Structural Features ◽  
Class I ◽  
Cell Surface Expression ◽  
Immune Recognition ◽  
Antigen Receptors ◽  
Class I Mhc ◽  
Mhc I

Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

HLA-E surface expression is independent of the availability of HLA class I signal sequence-derived peptides in human tumor cell lines

2005 ◽  
Vol 66 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Giulio Lelio Palmisano ◽  
Elisabetta Contardi ◽  
Anna Morabito ◽  
Vittoria Gargaglione ◽  
Giovanni Battista Ferrara ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Lines ◽  
Signal Sequence ◽  
Human Tumor ◽  
Hla Class I ◽  
Surface Expression ◽  
Class I ◽  
Tumor Cell Lines ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines

scholarly journals Tumorigenic Adenovirus Type 12 E1A Inhibits Phosphorylation of NF-κB by PKAc, Causing Loss of DNA Binding and Transactivation

2007 ◽  
Vol 82 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Hancheng Guan ◽  
Junfang Jiao ◽  
Robert P. Ricciardi
Keyword(s):  
Dna Binding ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Tumorigenic Cells

ABSTRACT Human adenovirus type 12 (Ad12) E1A protein (E1A-12) is the key determinant of viral tumorigenesis. E1A-12 mediates major histocompatibility complex class I (MHC-I) shutoff by inhibiting the DNA binding of the transcriptional activator NF-κB (p50/p65) to the class I enhancer. This enables Ad12 tumorigenic cells to avoid class I recognition and lysis by cytotoxic T lymphocytes. In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase A (PKAc) is essential for NF-κB DNA binding and transactivation activity. Treatment with H89 and knockdown of PKAc in cells led to the inhibition of phosphorylation at p50 Ser337 and p65 Ser276 and loss of DNA binding by NF-κB. Importantly, NF-κB phosphorylation by PKAc was repressed by tumorigenic E1A-12, but not by nontumorigenic Ad5 E1A (E1A-5). The stable introduction of E1A-12 into Ad5 nontumorigenic cells resulted in a decrease in the phosphorylation of NF-κB, loss of NF-κB DNA binding, and the failure of NF-κB to activate a target promoter, as well as diminution of MHC-I transcription and cell surface expression. Significantly, the amount and enzymatic activity of PKAc were not altered in Ad12 tumorigenic cells relative to its amount and activity in nontumorigenic Ad5 cells. These results demonstrate that E1A-12 specifically prevents NF-κB from being phosphorylated by PKAc.

Association of HLA-E Polymorphism with the Incidence of Severe Bacterial Infections in Sickle Cell Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2335-2335
Author(s):  
Ryad Tamouza ◽  
Catherine Fortier ◽  
Ibrahima Diagne ◽  
Dapa A. Diallo ◽  
Dominique Labie ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Bacterial Infections ◽  
Killer Cell ◽  
Group Versus ◽  
Hla Class I ◽  
Class I ◽  
Single Amino Acid ◽  
Cell Surface Expression ◽  
Infectious Episode

Abstract While it is commonly admitted that the susceptibility to severe infections (septicemia, meningitis, or osteomyelitis) in Sickle Cell Anemia (SCA) patients is a major cause of mortality and morbidity, these complications remains poorly explained. However, several lines of evidence highlight the involvement of an immunogenetic modulation, including both innate and adaptive immune responses. HLA-E belongs to the HLA-class I non-classical family and is ubiquitously expressed. HLA-E molecules bind either to self-peptides from the leader sequences of various HLA-class I molecules and thus modulate NK (Natural killer) cell activation/inhibition, or to the microbial derived-peptides from human viruses or bacteria to induce T cell responses. Only two functional alleles, HLA-E*0101 and HLA-E*0103, differing by a single amino acid substitution in the α2 heavy chain domain and by their cell surface expression level, have been reported so far. In order to evaluate whether the HLA-E polymorphism could influence the incidence of severe bacterial infections in SCA, we analyzed a cohort of 99 SCA patients living in Paris, but for the majority, originating from black Africa. All patients were older than 5 years of age at inclusion. Among the cohort, 51 presented at least one severe bacterial infection and 48 did not disclose any major infectious episode in their clinical history. Statistical analysis showed that the incidence of severe bacterial infections are high when the patient’s genotype was HLA-E*0101/E*0101 (47% in the first group versus 21% in the second group; χ2 = 7.54 p = 0.006, pc = 0.01, OR: 3.28, [95%CI = 1.28–9.07]), supporting a negative effect of this genotype. The genetic association herein found between HLA-E polymorphism and severe bacterial infections is of relevance, given the emerging evidence for the involvement of HLA-E molecules in pathogen-derived peptide presentation to human CD8+ T cells and hence in host response to pathogens. Furthermore, these data are in agreement with our previous findings in bone marrow transplantation settings, were the homozygous state for HLA-E*0101 allele is also a risk factor for early severe bacterial infections. Both situations by constitutively lowering the overall threshold of resistance to infection, might unmask anti infectious genetic factors normally silent.

CLL Cell Proliferation and IL-6 Production Are Regulated by CD160 - MHC Class I Interactions Offering New Therapeutic Targets.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1126-1126
Author(s):  
Jerome Giustiniani ◽  
Catherine Wiseman ◽  
Timothy Farren ◽  
John G. Gribben ◽  
Samir G. Agrawal
Keyword(s):  
Cell Proliferation ◽  
Mhc Class I ◽  
Killer Cell ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Class I ◽  
Cytotoxic Lymphocytes ◽  
Cell Surface Molecule ◽  
Mhc I ◽  
New Therapeutic Targets

Abstract We have previously demonstrated the expression of the Natural Killer cell (NK) marker CD160 in CLL, which is not expressed by normal B cells1. CD160 is a cell surface molecule expressed by human and mouse circulating cytotoxic lymphocytes and exhibits a broad specificity for major histocompatibility complex (MHC) class Ia and Ib molecules 2,3,4. Triggering of CD160 on NK cells leads to cell proliferation and IL-6 production5. IL-6 is a pleiotropic cytokine produced by a variety of cell types, including lymphocytes6. IL-6 expression has been associated with the development of lymphomas7, while higher serum IL-6 levels correlated with shorter survival in CLL8. Without stimulation, CLL cells secreted low basal levels of INF-γ (100pg/ml) and even lower levels of IL-2, IL-4, IL-6, IL-10 and TNF-α (< 50pg/ml) (cytokine bead array, BD Bioscience). Incubation with CL1-R2, an anti-CD160 monoclonal antibody, led to an increase in IL-6 alone (up to 1500pg/ml), which was associated with significant cell proliferation (detected by 3H incorporation) - median 100%, range 50 to 400% (n = 13). Different patterns of response were seen, with all cases showing proliferation to CL1-R2 alone and with the positive control pan anti-immunoglobulin Ab (anti-Ig Ab). In some cases, there was marked synergy between CL1-R2 and anti-Ig Ab. We found that the MEC I and MEC II B-cell lines, derived from a patient with prolymphocytic progression of CLL (DSMZ Institut), express CD160 and show CL1-R2 enhanced proliferation (30 to 55% increase). However, MEC I and MEC II only unregulated IL-10 production (13 to 33% increase). Interestingly, proliferation of CD160Neg Sanchez EBV-immortalized B-cells was inhibited when these cells were incubated with CHO-CD160 transfectants. This inhibition was reversed with an anti-CD160 Ab or anti-MHC-class I W6/32 Ab. The CD160-MHC-I interaction plays a role in CLL biology. MAb engagement of CD160 leads to: a direct proliferative signal; CD160-triggered production of IL-6 and IL-6 mediated effects; inhibition of a constitutive negative signal mediated via MHC-I molecules by their ligand CD160 (supported by the inhibition of the Sanchez cells by CD160 interaction with their MHC class I). The CD160-MHC class I axis represents a new pathway in CLL biology offering new therapeutic targets. This work also suggests a role for targeting the IL-6/IL-6R system in CLL - for example, with humanized anti-IL6 R (Actemra), already used for Castleman’s disease and Rheumatoid Arthritis. Fig 1: cells were incubated 72h in medium only or completed with IgG (control), anti-CD 160 antibody (CL1-R2), anti-IgM, G, A antibody (PAN antibody) or mix with PAN antibody and CL1-R2. For cytokine expriments, supernatants were taken after 24 hours. (left scale: CPM value, right scale: IL-6 concentration in pg/ml) Fig 1:. cells were incubated 72h in medium only or completed with IgG (control), anti-CD 160 antibody (CL1-R2), anti-IgM, G, A antibody (PAN antibody) or mix with PAN antibody and CL1-R2. For cytokine expriments, supernatants were taken after 24 hours. (left scale: CPM value, right scale: IL-6 concentration in pg/ml)

Mapping The HLA Ligandome Of Chronic Lymphocytic Leukemia – Towards Peptide Based Immunotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4123-4123 ◽  
Author(s):  
Daniel J. Kowalewski ◽  
Heiko Schuster ◽  
Claudia Berlin ◽  
Lothar Kanz ◽  
Helmut R. Salih ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
B Cells ◽  
Cd8 T Cells ◽  
Target Identification ◽  
Peptide Vaccine ◽  
Hla Class I ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
Class I ◽  
Hla Ligands

Abstract Accelerated clonal evolution and inhibition of immune effector functions are fundamental drawbacks of chemotherapeutic treatment of chronic lymphocytic leukemia (CLL) which contribute to increased clinical aggressiveness of relapsed disease. Anticancer immune responses such as graft versus leukemia effects and remissions after donor lymphocyte infusions, on the other hand, have been correlated to long-term CLL-free survival. Clonotype analysis in these cases suggested clonally expanded CD8+ T cells recognizing tumor associated antigens (TAAs) presented by HLA as mediators of the observed effects, thus making CLL an attractive target for peptide vaccine-based immunotherapy. We here report on our approach of direct isolation and identification of naturally processed and presented HLA ligands from tissues of interest by affinity chromatography and mass spectrometry. Comparative and semi-quantitative analysis of the HLA ligandomes of malignant and benign samples provided the rationale for the identification of ligandome derived TAAs (LiTAAs) and informed selection of peptide vaccine candidates. HLA class I ligands were isolated from MACS-sorted CLL cells as well as from normal B cells or PBMC of healthy volunteers using a standard immunoaffinity purification protocol. Liquid chromatography coupled mass spectrometry (LC-MS/MS) peptide analysis was performed on a LTQ Orbitrap hybrid mass spectrometer followed by database assisted processing of fragment spectra. Semi-quantitative data analysis provided information regarding the abundance of HLA ligands in the respective ligandomes. In addition, HLA surface expression on CLL cells and autologous normal B cells was quantitatively determined using a flow cytometric assay. Selected peptides were characterized functionally in IFN-γ ELISPOT assays using PBMC of healthy volunteers and CLL patients. No significant difference in HLA class I surface expression between CLL cells and autologous normal B cells was observed. So far, we were able to map the HLA class I peptidomes of 25 CLL patients and 35 healthy controls. In total, we were able to identify more than 25,000 different HLA ligands representing >8,500 different source proteins. More than 15,000 different ligands were derived from CLL cells representing a total of 6,500 source proteins. A twofold data mining approach was used to identify both, broadly presented LiTAAs suited for off-the-shelf vaccine development, and LiTAAs showing patterns of patient-specific overrepresentation allowing for actively personalized target identification. The former strategy enabled us to pinpoint the most frequently and abundantly represented targets from the bulk of over 2,000 source proteins, which were exclusively represented in the ligandomes of CLL cells. Several published CLL-associated antigens/epitopes were found to be presented (e.g. Pim-1 Oncogene, SET nuclear oncogene, Mucin-1), which served to validate our methodological approach as proof of principle. Beyond that we identified a vast array of novel proteins that are broadly and exclusively represented in the HLA peptidome of CLL cells. Based on these findings we selected HLA-A*02, A*03 and B*07 restricted ligands derived from top ranking LiTAAs (e.g.TP53I11, PARP3, CDCA7L) for immunological characterization. Using patient PBMC, we observed frequent, reproducible and specific immune recognition of the selected peptides by CD8+ T cells in recall ELISPOT assays. The observed reactivity to CLL-associated self-peptides indicates their potential as therapeutic vaccines while underlining the validity of our target identification and selection strategy. Currently we are expanding our analyses to cover a comprehensive spectrum of HLA types with the goal to develop a clinically applicable CLL-specific multi-peptide vaccine. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

1991 ◽  
Vol 174 (2) ◽  
pp. 371-379 ◽  
Author(s):  
S K Sanders ◽  
R O Fox ◽  
P Kavathas
Keyword(s):  
Amino Acids ◽  
Tertiary Structure ◽  
Mutational Analysis ◽  
Hla Class I ◽  
Antibody Binding ◽  
Variable Domain ◽  
Class I ◽  
Adhesion Assay ◽  
A Cell ◽  
Species Specific

The T cell co-receptor, CD8, binds to the alpha 3 domain of HLA class I (Salter, R.D., R.J. Benjamin, P.K. Wesley, S.E. Buxton, T.P.J. Garrett, C. Clayberger, A.M. Krensky, A.M. Norman, D.R. Littman, and P. Parham. 1990. Nature [Lond.]. 345:41; Connolly, J.M., T.A. Potter, E.M. Wormstall, and T.H. Hansen. 1988. J. Exp. Med. 168:325; and Potter, T.A., T.V. Rajan, R.F. Dick II, and J.A. Bluestone. 1989. Nature [Lond.]. 337:73). To identify regions of CD8 that are important for binding to HLA class I, we performed a mutational analysis of the CD8 molecule in the immunoglobulin (Ig)-like variable domain. Our mutational analysis was based on our finding that using a cell-cell adhesion assay murine CD8 (Lyt-2) did not bind to human class I. Since the interaction of human CD8 with HLA class I is species specific, we substituted nonconservative amino acids from mouse CD8 and analyzed the ability of the mutated CD8 molecules expressed in COS 7 cells to bind HLA class I-bearing B lymphoblastoid cells, UC. Mutants with the greatest effect on binding were located in a portion of the molecule homologous to the first and second hypervariable regions of an antibody combining site. In addition, a panel of 12 anti-CD8 monoclonal antibodies were used to stain the 10 CD8 mutants, and amino acids that affected antibody binding were localized on the crystal structure of the Bence-Jones homodimer, REI. Support for an Ig-like structure of CD8 can be found in the pattern of substitutions affecting antibody binding. This work supports the similar tertiary structure of the CD8 alpha-terminal domain and an Ig variable domain.

Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1723-1729 ◽  
Author(s):  
Massimo Vitale ◽  
Jacques Zimmer ◽  
Roberta Castriconi ◽  
Daniel Hanau ◽  
Lionel Donato ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Antigen Processing ◽  
Nk Cell ◽  
Hla Class I ◽  
Surface Expression ◽  
Class I ◽  
Inhibitory Receptor ◽  
Surface Receptors ◽  
Hla Class I Molecules

Natural killer (NK) cells are characterized by the ability to kill cells that lack HLA class I molecules while sparing autologous normal (HLA class I+) cells. However, patients with transporter-associated antigen processing (TAP) deficiency, though displaying strong reductions of HLA class I surface expression, in most instances do not experience NK-mediated autoimmune phenomena. A possible mechanism by which TAP−/− NK cells avoid autoreactivity against autologous HLA class I–deficient cells could be based on either quantitative or qualitative defects of surface receptors involved in NK cell triggering. In this study we show that NK cells derived from 2 patients with TAP2−/− express normal levels of all known triggering receptors. As revealed by the analysis of polyclonal and clonal NK cells, these receptors display normal functional capabilities and allow the killing of a panel of NK-susceptible targets, including autologous B-LCLs. On the other hand, TAP2−/− NK cells were unable to kill either allogeneic (HLA class I+) or autologous (HLA class I− ) phytohemagglutinin (PHA) blasts even in the presence of anti-HLA class I monoclonal antibody. These data suggest that TAP2−/− NK cells express still unknown inhibitory receptor(s) capable of down-regulating the NK cell cytotoxicity on binding to surface ligand(s) expressed by T cell blasts. Functional analyses, both at the polyclonal and at the clonal level, are consistent with the concept that the putative inhibitory receptor is expressed by virtually all TAP2−/− NK cells, whereas it is present only in rare NK cells from healthy persons. Another possibility would be that TAP2−/− NK cells are missing a still unidentified triggering receptor involved in NK cell-mediated killing of PHA blasts.

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