key: cord-0010428-evvvb6es
authors: Maudsley, D.John; Pound, John D.
title: Modulation of MHC antigen expression by viruses and oncogenes
date: 2004-12-10
journal: Immunol Today
DOI: 10.1016/0167-5699(91)90013-j
sha: 29e80b333620f3070e2350bae154205f48c71416
doc_id: 10428
cord_uid: evvvb6es

It is becoming increasingly clear that regulation of MHC antigen expression by viruses and oncogenes, leading to either immune evasion or autoimmunity, is widespread and important in disease. At a recent meeting, which brought together workers interested in tumour immunology, viral infection and the MHC, a number of mechanisms for the regulation of MHC antigen expression were revealed and the importance of balanced expression of MHC gene products to effective immunity was underlined.

The classical picture of major histocompatibility complex (MHC) antigen expression following infection is one of a dramatic rise, due primarily to an increase in production of interferons and other cytokines 1. This leads to enhanced recognition of infected cells by responding T cells, which recognize peptides of pathogen antigens in association with MHC antigens, and eradication of the infection. That this is not always the case is exemplified by hepatitis B virus (HBV) (G. Foster, London) which chronically infects some 200 million people worldwide. The ability of this virus to inhibit both alphainterferon (IFN-cl) production and the capacity of infected cells to respond to IFN are probably important in the maintenance of chronic infection. Treatment of chronic hepatitis with IFN-~ can lead to acute hepatitis followed by recovery, presumably as a result of enhancement of MHC class I expression by IFN-c~ leading to activation of HBV-specific T cells. also blocks transport of ~32-m, and hence of MHC class I antigens, to the cell surface. The result is a decrease in MHC antigen expression by a mechanism similar to that used by adenovirus 2: the E3-gene-encoded 19kDa protein of Ad2 binds to MHC class I heavy chains and prevents transport to the cell surface, which in turn results in reduced recognition and reduced lysis of infected cells by cytotoxic T cells 4.

Interestingly, the reduced MHC class I expression induced by CMV is also a signal for increased natural killer (NK) celt recognition and lysis (J. Grundy). This is reminiscent of the downregulation of class I by myc resulting in increased susceptibility to NK cell lysis (P. Schrier, Leiden; see below). Hence, the loss of MHC expression has both negative (for T cells) and positive (for NK cells) effects on the ability of the host to clear infected cells and the balance of these factors may determine the time and extent of recovery from infection. The increased susceptibility of CMV-infected cells to NK cell lysis is probably enhanced by an increase in expression of cell adhesion molecules, in particular lymphocyte function-associated molecule 3 (LFA-3) (CD58) and intercellular adhesion molecule 1 (ICAM-1) (CD54).

The role of cell adhesion molecules was a theme taken up for 

Transformation by viral oncogenes that downregulate either MHC class I or class II antigen expression (Adl2 Elaa; Ki-MuSV v-Ki-ras 24) results in the production of tumour cells that evade the immune system. What is the relative importance of class I versus class II and of the different genes within these regions? Transfection of the gross leukaemia-virus-infected AKR leukaemia cell line, K36.16, with either class I (H-2K k) or class II (I-E k) partially answers the question. Both antigens reduce tumourigenicity and both provide protection against future challenge with untransfected cells (R. James, Leicester). However, H-2Kk-transfected cells are still tumourigenic at high cell numbers and, unlike I-E k transfectants, do not provide any protection if given simultaneously with untransfected cells, suggesting that, while both are important, expression of class II antigens may be more effective at generating an immune response 2s.

Locus-specific effects are suggested by the effect of myc oncogenes; in a melanoma model, c-myc downregulates HLA-B in a locus-specific manner (P. Schrier). This appears to occur via the activation of a repressor that binds to the enh b regions and results in increased susceptibility to NK cell lysis. Resistance to NK cell lysis can be restored by treatment with IFN or transfection with HLA-B, both of which restore expression of HLA-B to the cell surface.

The clinical picture of MHC antigen expression on tumour cells is one of great diversity (P. Schrier; A. Nouri, London; R. Angus, Bristol). Loss of all MHC class I expression or allele-specific loss can occur; focal loss, that is where cells in some areas of a tumour do not express class I whereas other regions do, has also been described. Lack of expression of MHC class I antigen correlates with an absence of tumourinfiltrating lymphocytes. This type of information may have prognostic value in that, for example, in melanoma a high expression of MHC class I indicates a good prognosis while a high expression of MHC class II (though nonfunctional) appears to indicate a poor prognosis. There are a variety of phenotypes with respect to the ability of the cells to respond normally to IFN-y with increased MHC class I and class II antigen expression.

The size and complexity of the MHC was highlighted by J. Trowsdale (London). Although the role of interferons has been emphasized in this report, MHC antigen expression can be modulated by a wide range of cytokines, including tumour necrosis factor (TNF), IL-4, macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor 13 (TGF-13), TGF-c~ and epidermal growth factor (EGF) (I. Todd, Nottingham; F. Brennan, London; R. Darley, Warwick).

There is a growing recognition of the importance of the regulation of MHC antigen expression by viruses and turnout cells (especially by oncogenes), and its relevance to eradication of virus or tumour cells and development of autoimmune disease. Loss of MHC antigen expression from infected or transformed cells may be a strategy for survival and escape from the host immune system common to both viruses and tumour cells. However, the ideal levels of expression for the host are unclear since opposing factors, for example maximizing cytotoxic function and NK cell function, have to be balanced with the need to minimize tissue damage and induction of autoimmune reactions. 

Immune Responses, Virus Infection and Disease