scholarly journals Distinct Responsiveness of Tumor-Associated Macrophages to Immunotherapy of Tumors with Different Mechanisms of Major Histocompatibility Complex Class I Downregulation

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3057
Author(s):  
Adrianna Piatakova ◽  
Ingrid Polakova ◽  
Jana Smahelova ◽  
Shweta Dilip Johari ◽  
Jaroslav Nunvar ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Tumor Associated Macrophages ◽  
Mhc I ◽  
Vitro Assay ◽  
Histocompatibility Complex ◽  
Tumor Types

Tumor-associated macrophages (TAMs) plentifully infiltrate the tumor microenvironment (TME), but their role in anti-tumor immunity is controversial. Depending on the acquired polarization, they can either support tumor growth or participate in the elimination of neoplastic cells. In this study, we analyzed the TME by RNA-seq and flow cytometry and examined TAMs after ex vivo activation. Tumors with normal and either reversibly or irreversibly decreased expression of major histocompatibility complex class I (MHC-I) molecules were induced with TC-1, TC-1/A9, and TC-1/dB2m cells, respectively. We found that combined immunotherapy (IT), composed of DNA immunization and the CpG oligodeoxynucleotide (ODN) ODN1826, evoked immune reactions in the TME of TC-1- and TC-1/A9-induced tumors, while the TME of TC-1/dB2m tumors was mostly immunologically unresponsive. TAMs infiltrated both tumor types with MHC-I downregulation, but only TAMs from TC-1/A9 tumors acquired the M1 phenotype upon IT and were cytotoxic in in vitro assay. The anti-tumor effect of combined IT was markedly enhanced by a blockade of the colony-stimulating factor-1 receptor (CSF-1R), but only against TC-1/A9 tumors. Overall, TAMs from tumors with irreversible MHC-I downregulation were resistant to the stimulation of cytotoxic activity. These data suggest the dissimilarity of TAMs from different tumor types, which should be considered when utilizing TAMs in cancer IT.

scholarly journals TAPBPR mediates peptide dissociation from MHC class I using a leucine lever

2018 ◽  
Author(s):  
F. Tudor Ilca ◽  
Andreas Neerincx ◽  
Clemens Hermann ◽  
Ana Marcu ◽  
Stefan Stevanovic ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Dependent Manner ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Dissociation ◽  
Peptide Exchange

AbstractTapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.Impact StatementThis work demonstrates for the first time that the K22-D35 loop of TAPBPR is the essential region for mediating peptide exchange and peptide selection on major histocompatibility complex class I molecules.

Interferon beta modulates major histocompatibility complex class I (MHC I) and CD3-zeta expression in PC12 cells

2012 ◽  
Vol 513 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Rodrigo Fabrizzio Inácio ◽  
Renata Graciele Zanon ◽  
Liana Verinaud ◽  
Alexandre Leite Rodrigues de Oliveira
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Pc12 Cells ◽  
Interferon Beta ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex

scholarly journals A Mechanistic Basis for the Co-evolution of Chicken Tapasin and Major Histocompatibility Complex Class I (MHC I) Proteins

2013 ◽  
Vol 288 (45) ◽  
pp. 32797-32808 ◽  
Author(s):  
Andy van Hateren ◽  
Rachel Carter ◽  
Alistair Bailey ◽  
Nasia Kontouli ◽  
Anthony P. Williams ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Mechanistic Basis

scholarly journals Distinct Trafficking Pathways Mediate Nef-Induced and Clathrin-Dependent Major Histocompatibility Complex Class I Down-Regulation

2000 ◽  
Vol 74 (19) ◽  
pp. 9256-9266 ◽  
Author(s):  
Sylvie Le Gall ◽  
Florence Buseyne ◽  
Alicja Trocha ◽  
Bruce D. Walker ◽  
Jean-Michel Heard ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Down Regulation ◽  
Class I Mhc ◽  
Mhc I ◽  
Heavy Chains ◽  
Histocompatibility Complex

ABSTRACT The human immunodeficiency virus type 1 Nef protein alters the post-Golgi stages of major histocompatibility complex class I (MHC-I) biogenesis. Presumed mechanisms involve the disclosure of a cryptic tyrosine-based sorting signal (YSQA) located in the cytoplasmic tail of HLA-A and -B heavy chains. We changed this signal for a prototypic sorting motif (YSQI or YSQL). Modified HLA-A2 molecules, termed A2-endo, displayed constitutively low surface levels and accumulated in a region close to or within the Golgi apparatus, a behavior reminiscent of wild-type HLA-A2 in Nef-expressing cells. However, several lines of evidence indicate that the action of prototypic signals on MHC-I trafficking differs from that of Nef. Internalization of surface A2-endo was more rapid and was associated with efficient recycling to the surface. A transdominant-negative mutant of dynamin-1 inhibited A2-endo constitutive internalization and Nef-induced CD4 down-regulation, whereas it did not affect the activity of Nef on MHC-I. Moreover, trafficking of A2-endo was still affected by the viral protein, indicating additive effects of prototypic signals and Nef. Therefore, distinct trafficking pathways regulate clathrin-dependent and Nef-induced MHC-I modulation.

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 High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239

2010 ◽  
Vol 84 (10) ◽  
pp. 5443-5447 ◽  
Author(s):  
Thomas C. Friedrich ◽  
Shari M. Piaskowski ◽  
Enrique J. León ◽  
Jessica R. Furlott ◽  
Nicholas J. Maness ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Ex Vivo ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Human and simian immunodeficiency viruses (HIV and SIV) downregulate major histocompatibility complex class I (MHC-I) molecules from the surface of infected cells. Although this activity is conserved across viral isolates, its importance in AIDS pathogenesis is not clear. We therefore developed an assay to detect the level of MHC-I expression of SIV-infected cells directly ex vivo. Here we show that the extent of MHC-I downregulation is greatest in SIVmac239-infected macaques that never effectively control virus replication. Our results suggest that a high level of MHC-I downregulation is a hallmark of fast disease progression in SIV infection.

scholarly journals The N Terminus of Adenovirus Type 12 E1A Inhibits Major Histocompatibility Complex Class I Expression by Preventing Phosphorylation of NF-κB p65 Ser276 through Direct Binding

2010 ◽  
Vol 84 (15) ◽  
pp. 7668-7674 ◽  
Author(s):  
Junfang Jiao ◽  
Hancheng Guan ◽  
Andrew M. Lippa ◽  
Robert P. Ricciardi
Keyword(s):  
Amino Acids ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Adenovirus Type ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
N Terminus

ABSTRACT The immune-escape strategy employed by human oncogenic adenovirus type 12 (Ad12) involves downregulation of major histocompatibility complex class I (MHC-I) transcription by disabling the transactivator NF-κB (p50/p65). This is accomplished by the Ad12 E1A protein (E1A-12), which prevents NF-κB from becoming phosphorylated by the protein kinase A catalytic subunit (PKAc). In this study, we examined the interactions between E1A-12 and NF-κB. Our data show that an E1A-12 mutant retaining the N-terminal 66 amino acids was as effective as the wild-type E1A-12 protein (266 amino acids) in binding p65, preventing phosphorylation of p65-Ser276, and inhibiting transactivation. In contrast, the nontumorigenic adenovirus type 5 E1A protein (E1A-5) and other E1A-12 mutants lacking the N-terminal regions were severely defective in these activities. Further studies revealed that an N-terminal peptide consisting of residues 1 to 40 of E1A-12 was able to associate directly with p65 in vitro and prevent PKAc from phosphorylating p65-Ser276. In the absence of the N terminus, there is an almost complete loss of E1A-12 binding to p65. These findings provide solid evidence for the role of the E1A-12 N terminus as an NF-κB binding domain. Significantly, this study indicates that the E1A-12 N terminus prevents PKAc from gaining access to p65 to account for Ser276 hypophosphorylation. The E1A-12 N terminus interaction with p65 serves as a key explanation of how Ad12 downregulates MHC-I transcription and contributes to oncogenesis by escaping cytotoxic T lymphocytes.

scholarly journals GRP78, a Coreceptor for Coxsackievirus A9, Interacts with Major Histocompatibility Complex Class I Molecules Which Mediate Virus Internalization

2002 ◽  
Vol 76 (2) ◽  
pp. 633-643 ◽  
Author(s):  
Kathy Triantafilou ◽  
Didier Fradelizi ◽  
Keith Wilson ◽  
Martha Triantafilou
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Coxsackievirus A9

ABSTRACT It is becoming apparent that over the years cell infection by virus seems to have evolved into a multistep process in which many viruses employ distinct cell surface molecules for their attachment and cell entry. In this study the attachment and entry pathway of coxsackievirus A9 (CAV-9), a member of the Picornaviridae family, was investigated. It has been known that, although integrin αvβ3 is utilized as a receptor, its presence alone is insufficient for CAV-9 infection and that CAV-9 also requires a 70-kDa major histocompatibility complex class I (MHC-I)-associated protein (MAP-70) as a coreceptor molecule. We document by protein isolation and peptide sequencing that the 70-kDa protein is GRP78, a member of the heat shock protein 70 family of stress proteins. Furthermore we show by using fluorescence resonance energy transfer (FRET) that GRP78 is also expressed on the cell surface and associates with MHC-I molecules. In addition CAV-9 infection of permissive cells requires GRP78 and also MHC-I molecules, which are essential for virus internalization. The identification of GRP78 as a coreceptor for CAV-9 and the revelation of GRP78 and MHC-I associations have provided new insights into the life cycle of CAV-9, which utilizes integrin αvβ3 and GRP78 as receptor molecules whereas MHC-I molecules serve as the internalization pathway of this virus to mammalian cells.

scholarly journals Downregulation of major histocompatibility complex class I in bovine papillomas

2004 ◽  
Vol 85 (10) ◽  
pp. 2809-2814 ◽  
Author(s):  
E. H. Araibi ◽  
B. Marchetti ◽  
G. H. Ashrafi ◽  
M. S. Campo
Keyword(s):  
Immune Response ◽  
Major Histocompatibility Complex ◽  
Immune System ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Host Immune System ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex

Bovine papillomavirus (BPV) induces papillomas in cattle; in the great majority of cases, these regress due to the host immune response, but they can persist and progress to malignancy. Even in the absence of malignant transformation, BPV infection persists for a significant period of time before activation of the host immune system, suggesting that the host immune system is unaware of, or disabled by, BPV. E5 is the major oncoprotein of BPV, which, in addition to its transforming properties, downregulates the expression and transport to the cell surface of major histocompatibility complex class I (MHC I). Here, it is shown that co-expression of MHC I and E5 in papillomas caused by BPV-4 infection is mutually exclusive, in agreement with the inhibition of surface MHC I expression by E5 that is observed in vitro. The inhibition of MHC expression in E5-expressing papilloma cells could explain the long period that is required for activation of the immune response and has implications for the progression of papillomas to the malignant stage; absence of peptide presentation by MHC I to cytotoxic T lymphocytes would allow the infected cells to evade the host cellular immune response and allow the lesions to persist.

scholarly journals A Kmer-based paired-end read (KPR) de novo assembler and genotyper to genotype major histocompatibility complex class I (MHC-I) alleles for the dog

2020 ◽  
Author(s):  
Yuan Feng ◽  
William H. Hildebrand ◽  
Stephen M. Tompkins ◽  
Shaying Zhao
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
De Novo ◽  
Class I ◽  
Complex Class ◽  
Rna Seq ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex

AbstractThe major histocompatibility complex class I (MHC-I) genes are highly polymorphic among individuals. MHC-I genotyping is required for determining the antigen-binding specificity of each MHC-I molecule in an individual. Numerous tools have been developed for human MHC-I genotyping using deep sequencing data such as RNA-seq; however they do not work for the dog, due to very limited information for canine alleles. To address this issue, we developed a Kmer-based paired-end read (KPR) de novo assembler and genotyper, which first assemble paired-end RNA-seq reads mapped to the MHC-I regions into contigs de novo and then genotype each contig. Our KPR tools are validated by Sanger sequencing, simulation and published genotype data. Applying our KPR tools on the published RNA-seq data of 158 tumor and 64 normal samples from 158 dogs, we have achieved a genotyping success rate of 86%, which includes 133 tumor and 57 normal samples from 142 dogs. We have identified 39 known alleles and 83 new alleles of high confidence in these dogs, yielding a more comprehensive MHC-I allele diversity landscape for the dog.

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