Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) has been reported to interact with a wide spectrum of HLA class I (HLA-I) molecules, albeit with different affinities determined by allelic polymorphisms and conformational features. HLA-G dimerization and the presence of intracellular Cys residues in HLA-B7 have been shown to be critical for their recognition by LILRB1. We hypothesized that dimerization of classical HLA class Ia molecules, previously detected in exosomes, might enhance their interaction with LILRB1. A soluble LILRB1-Fc fusion protein and a sensitive cellular reporter system expressing a LILRB1-ζ chimera were employed to assess receptor interaction with different HLA class Ia molecules transfected in the human lymphoblastoid 721.221 cell line. Under these conditions, intracellular Cys residues and HLA-I dimerization appeared associated with increased LILRB1 recognition. On the other hand, a marginal interaction of LILRB1 with primary monocytic cells, irrespective of their high HLA-I expression, was enhanced by type I interferon (IFN). This effect appeared disproportionate to the cytokineinduced increase of surface HLA-I expression and was accompanied by detection of HLA class Ia dimers. Altogether, the results support that a regulated assembly of these noncanonical HLA-I conformers during the immune response may enhance the avidity of their interaction with LILRB1.Keywords: HLA class I dimers r LILRB1 r Macrophages r Type-I interferon Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), also termed ILT2, LIR-1 or CD85j, is an inhibitory receptor expressed by different leukocyte lineages which specifically interacts with HLA class I (HLA-I) molecules and the UL18 human cytomegalovirus glycoprotein [1,2]. Monocytic cells display higher cell surface levels of LILRB1 than lymphocytes, Correspondence: Miguel López-Botet e-mail: miguel.lopez-botet@upf.edu reflecting the involvement of different promoters in transcriptional regulation [3].LILRB1 comprises an extracellular region with four Iglike domains (D1-D4) and a cytoplasmic tail containing four immunoreceptor tyrosine-based inhibition motifs (ITIM) which recruit the SHP-1 tyrosine phosphatase [1,2]. Similarly to the role of other HLA-I inhibitory receptors in NK and T cells, LILRB1 contributes to control leukocyte activation and differentiation. * These authors contributed equally to this work. * * These authors contributed equally to this work as senior co-authors. LILRB1 engagement was reported to inhibit NK cell-mediated cytotoxicity and cytokine production [1,4,5] as well as TCR-and BCR-triggered responses [1,6,7]. In monocytes, co-engagement of LILRB1 with CD64 prevented tyrosine phosphorylation of the FcεR-I γ chain adaptor and intracellular Ca 2+ mobilization [8]. LILRB1 modulated monocyte-derived dendritic cell differentiation and suppressed in vitro osteoclast development induc...

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