REGULATION OF HLA CLASS-I AND CLASS-II EXPRESSION BY INTERFERONS AND INFLUENZA-A VIRUS IN HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

HLA class I and II molecules play a central role in regulating host im mune responses against microbial infections because they present forei gn antigens to CD8(+) and CD4(+) T lymphocytes, respectively. Many cyt okines, especially interferons (IFN), are known to upregulate human le ucocyte antigen (HLA) class I and II gene expression, but the kinetics , expression levels and viral regulation of HLA genes in primary human cells have not been well documented. Stimulation of peripheral blood mononuclear cells (PBMC) with IFN-alpha and IFN-gamma resulted in a 1. 5- to twofold increase in HLA class I and beta 2-microglobulin express ion in lymphocytes and monocytes. Lymphocytes did not express any dete ctable HLA class II either basally or after IFN induction. In monocyte s, instead, a high basal class II expression was found and it was furt her induced by IFN-alpha (up to twofold) and especially by IFN-gamma ( up to fivefold). In granulocyte-macrophage colony-stimulating factor ( GM-CSF) differentiated human macrophages, basal HLA class I and II pro tein expression levels were high but IFN-gamma stimulation was able to further enhance their expression. Accordingly, class I and II mRNA ex pression was elevated by IFN-gamma, whereas IFN-alpha practically had no effect on HLA class I mRNA levels. Influenza A virus infection of m acrophages resulted in temporary increases in HLA class I, beta 2-micr oglobulin and class II antigen expression. Neutralization of virus-ind uced IFN production by antibodies against type I and II IFNs prevented the virus-induced upregulation of HLA antigens. At late times of infe ction, as analysed by steady-state mRNA expression, both HLA class I a nd II mRNA were strongly reduced. These results suggest that IFNs are important regulators of HLA genes and responsible for a temporary incr ease in HLA antigen expression during influenza A virus infection.