Characterization of the Fas Ligand/Fas-Dependent Apoptosis of Antiretroviral, Class I MHC Tetramer-Defined, CD8+CTL by In Vivo Retrovirus-Infected Cells

Equine herpesvirus 1 (EHV-1) uses equine major histocompatibility complex class I (MHC class I) as an entry receptor. Exogenous expression of equine MHC class I genes in murine cell lines confers susceptibility to EHV-1 infection. To examine the in vivo role of equine MHC class I as an entry receptor for EHV-1, we generated transgenic (Tg) mice expressing equine MHC class I under the control of the CAG promoter. Equine MHC class I protein was expressed in the liver, spleen, lung, and brain of Tg mice, which was confirmed by Western blot. However, equine MHC class I antigen was only detected in bronchiolar epithelium and not in other tissues, using the immunofluorescence method employed in this study. Both Tg and wild-type (WT) mice developed pneumonia 3 days after intranasal infection with EHV-1. The bronchiolar epithelial cells of Tg mice showed more severe necrosis, compared with those in WT mice. In addition, the number of virus antigen-positive cells in the lungs was higher in Tg mice than in WT mice. These results suggest that exogenous expression of equine MHC class I renders mice more susceptible to EHV-1 infection.

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Most viral peptides displayed by class I MHC on infected cells are immunogenic

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1815239116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 3112-3117 ◽

Cited By ~ 34

Author(s):

Nathan P. Croft ◽

Stewart A. Smith ◽

Jana Pickering ◽

John Sidney ◽

Bjoern Peters ◽

...

Keyword(s):

Infected Mouse ◽

High Resolution Mass Spectrometry ◽

Peptide Sequencing ◽

Class I ◽

Class I Mhc ◽

Wide Range ◽

Multiple Virus ◽

Infected Cells ◽

High Fraction ◽

Mouse Cells

CD8+ T cells are essential effectors in antiviral immunity, recognizing short virus-derived peptides presented by MHC class I (pMHCI) on the surface of infected cells. However, the fraction of viral pMHCI on infected cells that are immunogenic has not been shown for any virus. To approach this fundamental question, we used peptide sequencing by high-resolution mass spectrometry to identify more than 170 vaccinia virus pMHCI presented on infected mouse cells. Next, we screened each peptide for immunogenicity in multiple virus-infected mice, revealing a wide range of immunogenicities. A surprisingly high fraction (>80%) of pMHCI were immunogenic in at least one infected mouse, and nearly 40% were immunogenic across more than half of the mice screened. The high number of peptides found to be immunogenic and the distribution of responses across mice give us insight into the specificity of antiviral CD8+ T cell responses.

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Characterization of a Murine Cytomegalovirus Class I Major Histocompatibility Complex (MHC) Homolog: Comparison to MHC Molecules and to the Human Cytomegalovirus MHC Homolog

Journal of Virology ◽

10.1128/jvi.72.1.460-466.1998 ◽

1998 ◽

Vol 72 (1) ◽

pp. 460-466 ◽

Cited By ~ 44

Author(s):

Tara L. Chapman ◽

Pamela J. Bjorkman

Keyword(s):

Major Histocompatibility Complex ◽

Heavy Chain ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Endogenous Peptides ◽

Β2 Microglobulin ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Infected Cells

ABSTRACT Both human and murine cytomegaloviruses (HCMV and MCMV) down-regulate expression of conventional class I major histocompatibility complex (MHC) molecules at the surfaces of infected cells. This allows the infected cells to evade recognition by cytotoxic T cells but leaves them susceptible to natural killer cells, which lyse cells that lack class I molecules. Both HCMV and MCMV encode class I MHC heavy-chain homologs that may function in immune response evasion. We previously showed that a soluble form of the HCMV class I homolog (UL18) expressed in Chinese hamster ovary cells binds the class I MHC light-chain β2-microglobulin and a mixture of endogenous peptides (M. L. Fahnestock, J. L. Johnson, R. M. R. Feldman, J. M. Neveu, W. S. Lane, and P. J. Bjorkman, Immunity 3:583–590, 1995). Consistent with this observation, sequence comparisons suggest that UL18 contains the well-characterized groove that serves as the binding site in MHC molecules for peptides derived from endogenous and foreign proteins. By contrast, the MCMV homolog (m144) contains a substantial deletion within the counterpart of its α2 domain and might not be expected to contain a groove capable of binding peptides. We have now expressed a soluble version of m144 and verified that it forms a heavy chain–β2-microglobulin complex. By contrast to UL18 and classical class I MHC molecules, m144 does not associate with endogenous peptides yet is thermally stable. These results suggest that UL18 and m144 differ structurally and might therefore serve different functions for their respective viruses.

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Targeting mutant p53-expressing tumours with a T cell receptor-like antibody specific for a wild-type antigen

Nature Communications ◽

10.1038/s41467-019-13305-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Lionel Low ◽

Angeline Goh ◽

Joanna Koh ◽

Samantha Lim ◽

Cheng-I Wang

Keyword(s):

Cell Receptor ◽

Class I ◽

Human Antibody ◽

Mutant P53 ◽

Wild Type ◽

Class I Mhc ◽

Type Antigen ◽

Wide Range

AbstractAccumulation of mutant p53 proteins is frequently found in a wide range of cancers. While conventional antibodies fail to target intracellular proteins, proteosomal degradation results in the presentation of p53-derived peptides on the tumour cell surface by class I molecules of the major histocompatibility complex (MHC). Elevated levels of such p53-derived peptide-MHCs on tumour cells potentially differentiate them from healthy tissues. Here, we report the engineering of an affinity-matured human antibody, P1C1TM, specific for the unmutated p53125-134 peptide in complex with the HLA-A24 class I MHC molecule. We show that P1C1TM distinguishes between mutant and wild-type p53 expressing HLA-A24+ cells, and mediates antibody dependent cellular cytotoxicity of mutant p53 expressing cells in vitro. Furthermore, we show that cytotoxic PNU-159682-P1C1TM drug conjugates specifically inhibit growth of mutant p53 expressing cells in vitro and in vivo. Hence, p53-associated peptide-MHCs are attractive targets for the immunotherapy against mutant p53 expressing tumours.

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Cloning and characterization of class I Mhc genes of the zebrafish, Brachydanio rerio

Immunogenetics ◽

10.1007/bf00178581 ◽

1995 ◽

Vol 42 (2) ◽

Cited By ~ 45

Author(s):

Hiroaki Takeuchi ◽

Felipe Figueroa ◽

Colm O'hUigin ◽

Jan Klein

Keyword(s):

Class I ◽

Brachydanio Rerio ◽

Class I Mhc ◽

Mhc Genes

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Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

Journal of Experimental Medicine ◽

10.1084/jem.166.6.1716 ◽

1987 ◽

Vol 166 (6) ◽

pp. 1716-1733 ◽

Cited By ~ 61

Author(s):

J S Weber ◽

G Jay ◽

K Tanaka ◽

S A Rosenberg

Keyword(s):

T Cells ◽

Mhc Class I ◽

Interleukin 2 ◽

Class I ◽

High Dose ◽

Class I Mhc ◽

High Doses ◽

I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

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