The Influence of Cytomegalovirus on Expression of HLA‐G and its Ligand KIR2DL4 by Human Peripheral Blood Leucocyte Subsets

Abstract

HLA-G is a non-classical class I HLA antigen, normally expressed in high levels only on extravillous cytotrophoblast. It has immunosuppressive properties in pregnancy and has also been found to be upregulated on leucocytes in viral infection. In this study, proportions of all leucocyte subsets expressing HLA-G were found to be low in healthy subjects positive or negative for cytomegalovirus (CMV). Significantly greater proportions of CD4+ CD69+ and CD56+ T cells expressed HLA-G compared to other T cells. However, following stimulation with CMV antigens or intact CMV, proportions of CD4+, CD8+, CD69+ and CD56+ T cells, and also B cells expressing HLA-G, were significantly increased in CMV+ subjects. Despite some subjects having alleles of HLA-G associated with high levels of expression, no relationship was found between HLA-G genotype and expression levels. Purified B cells from CMV+ subjects stimulated in mixed culture with CMV antigens showed significantly increased HLA-G mRNA expression by real-time polymerase chain reaction. Serum levels of soluble HLA-G were similar in CMV- and CMV+ subjects but levels in culture supernatants were significantly higher in cells from CMV+ than from CMV- subjects stimulated with CMV antigens. The HLA-G ligand KIR2DL4 was mainly expressed on NK cells and CD56+ T cells with no differences between CMV+ and CMV- subjects. Following stimulation with IL-2, an increase in the proportion of CD56+ T cells positive for KIR2DL4 was found, together with a significant decrease in CD56dimCD16+ NK cells. The results show that CMV influences HLA-G expression in healthy subjects and may contribute to viral immune evasion.

Changes in HLA-G Expression by Leucocyte Subsets Following Renal Transplantation and the Effect of Immunosuppressive Drugs on Leucocyte HLA-G Expression in Vitro

“…A proportion of the HLA-G+ CD4+ T cells, particularly of the CD69+ subset, may have been Tregs and it has been suggested that sHLA-G may participate in graft acceptance through induction of Tregs [39]. In our previous work with healthy subjects, only around 1-2% of Tregs expressed HLA-G and this proportion was decreased further following stimulation with CMV antigens [36]. Alternative possibilities are that HLA-G+ CD4+ T cells are a component of the alloreactive population or are induced following immunosuppressive drug treatment.…”

“…Such changes in HLA-G expression may potentially also be related to the immunosuppressive drug treatment or other factors, such as activation of cytomegalovirus (CMV). In previous work in healthy subjects we have shown that stimulation of peripheral blood mononuclear cells with CMV antigens resulted in increased proportions of leucocytes expressing HLA-G, particularly B cells and CD56+ T cells [36]. The aims of the present experiments were to assess any post-transplant changes in HLA-G expression by a range of leucocyte subsets in renal transplant patients.…”

The role of HLA‐G in parasitic diseases

“…Besides, NK cells express the KIR2DL4 receptor, another putative HLA‐G receptor. Notwithstanding, the binding of sHLA‐G to KIR2DL4 does not affect NK cytotoxicity …”

“…Notwithstanding, the binding of sHLA-G to KIR2DL4 does not affect NK cytotoxicity. 63 Although the expression of ILT2 in B-cells has long been reported, the function of HLA-G on B cells has recently been investigated. HLA-G inhibits the proliferation, differentiation and antibody secretion of activated B cells from peripheral blood and secondary lymphoid organs through interaction with ILT2.…”

Conserved and variable natural killer cell receptors: diverse approaches to viral infections

“…Although LILRB1 is not conserved between humans and the common chimpanzee, KIR2DL4 is highly conserved, a striking observation considering the rapid evolution of the KIR locus . HLA‐G can be up‐regulated during viral infections such as CMV, hepatitis B virus (HBV) and HCV . This raises the intriguing possibility that the HLA‐G–KIR2DL4 interaction may have an important biological role that has led to their conservation between humans and chimpanzees.…”