Interactions between HLA-G and HLA-E in Physiological and Pathological Conditions

Abstract

HLA-G and HLA-E are immunoregulatory molecules that belong to HLA-Ib family. The role of these molecules in the control of the immune response has been extensively analyzed, both in physiological and pathological conditions. We have here summarized data present in the literature regarding the interaction of these molecules in different settings. These data suggested that HLA-G and -E co-operate in physiological conditions (i.e., establishment of an immune tolerance at maternal/fetal interface during pregnancy), whereas their role in the course of tumors or autoimmune/inflammatory diseases may be different or even opposite. Future studies aimed at investigating the interaction between HLA-G and HLA-E will help to clarify mechanism(s) underlying the regulation of immune effector cells in health and disease.

Keywords: HLA-E; HLA-G; autoimmune disease; tumor; viral infections.

Figure 1

Interactions between HLA-G and HLA-E in the control of the immune response. During pregnancy, HLA-G and -E are both expressed by trophoblast cells and co-operate in the inhibition of NK cell functions, by interacting with ILT2 and CD94/NKG2A receptors, respectively (A). In different tumors, the loss of HLA-class Ia molecules activate NK cells through KIR ligand mismatch. HLA-G and -E co-operate in the inhibition of activated NK cells in the tumor microenvironment, facilitating the escape of tumor cells from NK cell recognition (B). In renal cell carcinoma, HLA-G expression correlates with worse prognosis, whereas HLA-E expression represents a favorable prognostic marker. We can speculate that in this case HLA-G preferentially interacts with inhibitory receptors on NK cells and CTL, whereas HLA-E possibly interacts with CD94/NKG2C activating receptor on immune effector cells (C). On the contrary, in laryngeal carcinoma, HLA-G predicts a good prognosis, whereas HLA-E is associated with worse prognosis. In this case, we speculate that HLA-G may predominantly interact with KIR2DL4 activating receptor, whereas HLA-E interacts with CD94/NKG2A inhibitory receptor on NK cells and CTL (D). In multiple sclerosis patients, HLA-G and HLA-E are expressed and released by resident cells in the central nervous system (CNS), and both soluble molecules co-operate in the inhibition of NK cells and CTL function, by interacting with inhibitory receptors (E).