Immunomodulatory properties of HLA-G in infectious diseases

Abstract

HLA-G is a nonclassical major histocompatibility complex molecule first described at the maternal-fetal interface, on extravillous cytotrophoblasts. Its expression is restricted to some tissues in normal conditions but increases strongly in pathological conditions. The expression of this molecule has been studied in detail in cancers and is now also beginning to be described in infectious diseases. The relevance of studies on HLA-G expression lies in the well known inhibitory effect of this molecule on all cell types involved in innate and adaptive immunity, favoring escape from immune control. In this review, we summarize the features of HLA-G expression by type of infections (i.e, bacterial, viral, or parasitic) detailing the state of knowledge for each pathogenic agent. The polymorphism, the interference of viral proteins with HLA-G intracellular trafficking, and various cytokines have been described to modulate HLA-G expression during infections. We also discuss the cellular source of HLA-G, according to the type of infection and the potential role of HLA-G. New therapeutic approaches based on synthetic HLA-G-derived proteins or antibodies are emerging in mouse models of cancer or transplantation, and these new therapeutic tools may eventually prove useful for the treatment of infectious diseases.

Figure 1

Causes and consequences of HLA-G modulation in infectious diseases. Positive and negative effects of HLA-G are shown in blue and red, respectively. Parasites, bacteria, or viruses induce the secretion of various cytokines, including IL-10 and interferon (-γ for bacterium and IFN-α and -β for virus). These cytokines upregulate the expression or secretion of HLA-G. In addition, IL-10 induces IL-10-producing human dendritic cells (DCs), termed DC-10, expressing HLA-G and ILT4. HLA-G induces tolerogenic DC in addition to DC-10 and regulatory cells via direct interaction with ILT2 and/or ILT4. HLA-G, through direct interaction with ILT2, inhibits the function of T and NK cells and B cells, whereas it inhibits the function of granulocytes and myeloid DC via direct interaction with ILT4. Indirect effects of HLA-G are mediated by the induction of HLA-E cell surface expression, which inhibits CD94/NKG2a on NK and T cells. The consequence of HLA-G action is a downregulation of innate and adaptive immunity.