Indoleamine 2,3 dioxygenase and human leucocyte antigen‐G inhibit the T‐cell alloproliferative response through two independent pathways

Abstract

Both human leucocyte antigen (HLA)-G and indoleamine 2,3 dioxygenase (IDO) are key molecules involved in immune tolerance. HLA-G is a non-classical HLA class I molecule that can be expressed in both membrane-bound (HLA-G1) and soluble (HLA-G5) forms, both of which exhibit tolerogenic properties via interaction with inhibitory receptors present on natural killer (NK) cells, T cells and antigen-presenting cells (APC). IDO is an enzyme that acts by depleting the surrounding microenvironment of the essential amino acid, tryptophan, thereby inhibiting T-cell proliferation. Our present study was aimed at analysing the potential link that may exist between IDO and HLA-G. Our results showed that during allogeneic reactions, soluble HLA-G expression was not regulated by the addition of IDO substrate (i.e. tryptophan), metabolite (i.e. kynurenine) or inhibitor (i.e. 1-methyl-tryptophan), that IDO activity was not altered by HLA-G5 treatment, and that HLA-G5-mediated inhibition of the T-cell alloproliferative response was neither affected by the presence of tryptophan and kynurenine nor reversed after IDO activity blockage, demonstrating that HLA-G5 can exert its function in the absence of functional IDO. Similarly, inhibition of the T-cell alloresponse, induced by HLA-G1-expressing antigen-presenting cells, was not altered by IDO metabolites or inhibitor. Taken together, these findings show that the function and expression of IDO and HLA-G5 are not mutually influenced, but rather inhibit the T-cell alloproliferative response through two independent pathways. IDO and HLA-G are thus complementary for inducing and maintaining immune tolerance in physiological (pregnancy) and pathological (tumour and allograft) situations.