Dimerization Of Soluble HLA-G By IgG-Fc Fragment Augments ILT2-mediated Inhibition Of T-cell Alloresponse

HLA-G, a non-classical HLA class I molecule, induces a wide range of tolerogenic immunological effects via interaction with its inhibitory receptors. However, recent studies show that HLA-G dimer formation is essential to bind to its receptors and exhibit its effects. In this study, a soluble divalent HLA-G/IgG molecule (sHLA-G dimer) was constructed. Its inhibitory effect on T-cell alloresponse was studied with mixed lymphocyte reaction (MLR) in vitro, which was set up by mixing inactivated T1 cells with HLA-mismatched peripheral blood lymphocytes (PBLs) in the presence or absence of the sHLA-G dimer. The results show that sHLA-G dimer inhibits T-cell alloresponse by reducing proliferation of both CD4+ and CD8+ T cells and suppressing generation of allo-reactive CTLs at nanomole concentration. The inhibition of the sHLA-G dimer is observed to be more effective than that of sHLA-G monomer. Our results also indicate sHLA-G dimer up-regulates inhibitory receptor ILT2 on allo-reactive CD8+ T cells, which contributes to the significant inhibition on T-cell alloresponse. The sHLA-G dimer molecule may have implications for allo-transplantation.